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Breast Cancer Survival, Survival Disparities, and Guideline-Based Treatment

Deirdre a. hill.

1 Internal Medicine Department, University of New Mexico School of Medicine, and Comprehensive Cancer Center, University of New Mexico, Albuquerque, NM

Sarah Friend

2 Department of Hematology/Oncology, Emory University School of Medicine, Atlanta, GA

Lesley Lomo

3 Department of Pathology, University of New Mexico, Albuquerque, NM

Charles Wiggins

Eric prossnitz.

4 Department of Molecular Medicine, University of New Mexico, Albuquerque, NM

Melanie Royce

The role of appropriate therapy in breast cancer survival and survival disparities by race/ethnicity have not been fully elucidated. We investigated whether guideline-inconsistent therapy contributed to survival differences overall and among Hispanics relative to non-Hispanic white (NHW) women in a case-cohort study.

This study included a 15% random sample of female invasive breast cancer patients diagnosed from 1997–2009 in 6 New Mexico counties and all deaths due to breast cancer-related causes. Information was obtained from comprehensive medical chart reviews. National Comprehensive Cancer Network (NCCN ® ) guideline-consistent treatment was assessed among white women aged < 70 who were free of contraindications for recommended therapy, had stage I–III tumors, and had survived at least 12 months. Hazard ratios (HRs) and 95% confidence intervals (CIs) for breast cancer death were estimated using Cox proportional hazards models.

The median survival was 101 months. The included women represented 4635 patients and 449 breast cancer deaths. Women who met specific NCCN treatment criteria but did not receive radiotherapy (HR 2.3; 95% CI 1.2–4.4) or endocrine therapy (HR 2.0; 95% CI 1.0–4.0) had an increased risk of breast cancer death relative to those who did receive these therapies. Guideline-consistent therapy receipt did not differ between Hispanic and NHW women for chemotherapy (84.2% vs. 81.3%, respectively), radiotherapy (89.2% vs. 91.1%, respectively) or endocrine therapy (89.2% vs. 85.8%, respectively), and it did not influence Hispanic survival disparities.

Conclusions

Guideline-concordant receipt of radiotherapy and endocrine therapy contributed to survival as strongly as other established prognostic indicators. Hispanic survival disparities in this population do not appear to be attributable to treatment differences.

Introduction

Breast cancer treatment guidelines, such as those developed by the National Comprehensive Cancer Network® (NCCN®)[ 1 ], the National Cancer Institute (NCI)[ 2 ], the St. Gallen conference [ 3 ] and others, using the highest levels of evidence and consensus expert opinion, have evolved to play a definitive role in the selection of appropriate adjuvant therapy following breast cancer surgery. Only a handful of studies have evaluated the influence of guideline-concordant therapy on breast cancer survival: in those investigations, breast cancer patients who received treatment consistent with guidelines had a reduced risk of mortality [ 4 ], whereas those who did not were at an increased risk of recurrence [ 5 ] or overall mortality [ 6 ].

Guideline-consistent treatment may be relatively underutilized among underserved populations such as Hispanic or Black women. In several studies, such women have been less likely than other women to receive radiation after breast-conserving surgery or other adjuvant therapy [ 7 – 10 ], despite guideline eligibility. Lack of receipt of appropriate therapy is of great concern in light of the persistently elevated breast cancer-specific mortality in these populations[ 11 , 12 ]. Few studies have quantified the influence of differences in treatment on the gap in outcomes by race or ethnicity[ 13 ]. Therapy receipt, if a contributor to breast cancer survival disparities, is amenable to intervention at the patient, provider, and system levels[ 14 – 16 ].

Despite widespread dissemination of clinical practice guidelines, variations in breast cancer treatment may be attributable in some part to patient contraindications, such as comorbid conditions, or possibly to early mortality. In a population-based case-cohort study in New Mexico, using a framework that accounted for clinical reasons for the non-receipt of therapy, we sought to determine whether women who received guideline-inconsistent therapy had an increased risk of breast cancer-specific mortality and whether differential receipt of guideline-based treatment contributed to the 1.7-fold increased risk of breast cancer-specific mortality in Hispanic women.

Patients and Methods

We conducted a population-based case-cohort study of breast cancer-specific survival among all first invasive breast cancer cases diagnosed from 1997–2009 among white female residents of six New Mexico counties (Bernalillo, Sandoval, Santa Fe, Socorro, Torrance, and Valencia). We used information from the New Mexico Tumor Registry (NMTR), a National Cancer Institute (NCI)-funded Surveillance Epidemiology End Results (SEER) site, to randomly select 15% of all first invasive breast cancer diagnoses (sub-cohort) and all deaths due to breast cancer-related causes (cases) among all incident diagnoses (not diagnosed by autopsy or death certificate).

We excluded women who were not residents of New Mexico, who had an unknown cause of death, or who received treatment outside the six-county region (thus precluding the treatment assessment). Hispanic ethnicity was defined using the North American Association of Central Cancer Registries (NAACR) algorithm utilized in SEER, with the exclusion of women identified only by Spanish surname. Analyses were restricted to women with stage I–III disease who survived at least 12 months post-diagnosis, thus allowing a modicum of time for guideline-adherent treatment to be received. In accordance with NCCN guidelines, the included women were also restricted to age < 70 at diagnosis, which minimized non-receipt due to comorbidity or life expectancy ( Figure 1 ).

Eligibility and Inclusion in Analyses: Population-Based Invasive Breast Cancer Cases Diagnosed from 1997–2009 in six New Mexico counties.

Data Collection

Initial inpatient and outpatient providers were identified through SEER. Because the counties surrounding the six counties are sparsely populated, most residents receive medical care within the study area. Medical record reviews were conducted by SEER-trained certified tumor registrars (CTR) or a registered health information technologist. Paper and electronic medical records were reviewed for surgical oncology, radiation oncology, medical oncology, and long-term follow-up care. SEER funding allows collection of only the first course of therapy[ 17 , 18 ], resulting in under ascertainment of treatment[ 19 , 20 , 18 ]. Thus, additional providers identified through referral notes, pathology information, or hospital or clinic record searches were also reviewed. Medical records were sought at an average of 2.3 hospitals or clinics per woman. The data collected included standard demographic variables, diagnosis information (tumor size, lymph node status, tumor receptor status), and detailed information about treatment, including surgery, neoadjuvant and adjuvant chemotherapy, radiation, endocrine, and biological therapy (types, dates of receipt, doses, and agents). For women who had bilateral synchronous cancers diagnosed, only the most advanced cancer was included. Information was sought regarding physician-stated contraindications for each therapy, patient refusals of treatment, and comorbidities in the Charlson Index[ 21 , 22 ]. Oncotype DX Breast Cancer Assay[ 23 ] (Genomic Health, Redwood City, CA) results were abstracted when available. SEER data (limited to treatment initiation only) were the sole source of information for 73/663 (11.0%) of the women who received chemotherapy, 71/703 (10.0%) who received radiation, and 50/638 (7.8%) who received endocrine therapies. The positive predictive value for SEER data in comparison with medical record reviews or claims data is high[ 18 ]. Medical chart reviews yielded information that SEER did not (SEER treatment initiation sensitivity: chemotherapy (89.3%), radiotherapy (76.1%), endocrine therapy (55.0%)). For n=45 women (included in the totals above), medical records were unavailable, and SEER was the sole source of information used.

Follow-up and ascertainment of vital status

Women were followed through January 1, 2013. Vital status and cause of death were determined by the New Mexico Tumor Registry, using probabilistic matching to the New Mexico State Vital Statistics Bureau files, and the National Death Index of the National Center for Health Statistics. Vital status was verified by the submission of files to the Centers for Medicare and Medicaid Services. Because Hispanic women have a lower age-adjusted all-cause mortality rate than non-Hispanic white women, which can mask any elevation in cause-specific mortality rates, only deaths attributed to breast cancer as an underlying cause on the death certificate were included as events in the analysis.

Classification of Therapy Receipt according to National Comprehensive Cancer Network Guidelines

NCCN Clinical Practice Guidelines in Oncology® (NCCN Guidelines®) for breast cancer for 1997 through 2009[ 1 ] were reviewed to determine eligibility for treatment. Women were considered eligible for a particular therapy if their tumor characteristics met the guideline criteria for the year of diagnosis: category 1 for diagnoses from 1997 to 1999 and category 1 or 2A for 2000–2009 diagnoses ( Figure 2 ). Women who had any physician-noted contraindications for a therapy were omitted from the analyses of guideline-concordant receipt of that therapy. Women missing tumor characteristics necessary to determine eligibility (< 5%; Table 1 ) were also excluded from the analysis of that therapy. For chemotherapy only, women with the following contraindications noted in medical records were also excluded from the guideline analysis: history of previous malignancy, heart failure, myocardial infarction, cerebrovascular accident, or an Oncotype DX score < 18. Women who met the guideline criteria for each therapy were classified as having received treatment if medical chart review yielded details of treatment (or if indicated in SEER records) and not treated otherwise.

National Comprehensive Cancer Network (NCCN) Guidelines for Invasive Breast Cancer Adjuvant Care, 1997–2009

Abbreviations: HR hormone receptor, LN lymph node

Characteristics of incident invasive breast cancer cases who survived 12 or more months (Subcohort – 15% sample of all eligible cases).

Statistical Analysis

Cox proportional hazards models for case-cohorts were utilized [ 24 ] to calculate hazard ratios (HRs) and 95% confidence intervals (CIs) using an alpha level of .05. Specifically, women in the subcohort were weighted by the inverse of the sampling fraction (100%/15% = 6.67). Women in the subcohort entered the study at 12 months post-diagnosis (staggered entry time) and were followed until death, loss to follow-up, or January 1, 2013. Death due to breast cancer-related causes was the end point of interest, and all other events were censored. Time to event was measured in months. To determine whether non-receipt of therapy was attributable in part to early mortality, we conducted additional analyses, restricting entry time to 24 months post-diagnosis. Confounding by indication for therapy was addressed by restricting each analysis only to women who met the NCCN guidelines for that therapy (women with contraindications were excluded). Such restriction to only one level of the confounder eliminates confounding. The contribution of guideline-concordant therapy to breast cancer survival was evaluated using likelihood ratio tests. To determine whether disparate breast cancer survival differences in Hispanic women were attributable in part to the differential receipt of therapy, we evaluated the change in hazard ratio with the addition of variables for appropriate treatment. Any decline in the hazard ratio for Hispanic ethnicity with the inclusion of treatment in the model would suggest that treatment was a contributor to survival disparities[ 25 , 26 ]. We also estimated whether the effect of therapy on survival differed among Hispanic women by including the main effects of Hispanic ethnicity and guideline-adherent therapy and an interaction term in Cox regression models. We calculated the Hispanic survival hazard ratio among strata defined by guideline-adherent treatment vs not. The proportional hazards assumption was verified using Schoenfeld residuals [ 27 ]. Analyses were adjusted for age (5-year age groups), tumor size (<1 cm, 1–<3 cm, 3–<5 cm, and ≥ 5 cm; skin/chest wall involvement, cut points determined by NCCN treatment guidelines- Figure 2 ), positive lymph nodes (0, 1–3, 4+) tumor grade (1, 2, 3/4), estrogen receptor (ER) status, progesterone receptor (PR) status, Her2/neu status, and Hispanic ethnicity. All analyses were conducted in SAS v 9.4 (Cary, N.C.), and multivariate-adjusted survival estimates were graphed using R software v 3.3.3 (Vienna, Austria). We received institutional review board approval for the study from the University of New Mexico Health Sciences Center under a Health Insurance Portability and Accountability Act (HIPAA) waiver of consent for previously collected data.

This study included 695 women selected from the cohort (representing 4635 women in the full cohort, when weighted by 6.67, the inverse of the 15% sampling fraction) and 449 who died of breast cancer-related causes ( Figure 1 ). On average, women who died were more likely to be younger, and as expected, had tumor characteristics associated with a poorer prognosis ( Table 1 ). The median survival in the cohort was 101 months (8.4 years) post-diagnosis. Hispanic women comprised 25.3% of the cohort and 34.7% of breast cancer deaths. Overall, Hispanic women were 1.7-fold more likely to die of breast cancer-specific causes than non-Hispanic white women (95% CI 1.1–2.9).

We first examined outcomes among the women eligible for each treatment under NCCN guidelines. Among women who met the guideline criteria for chemotherapy ( Figure 2 ), those who did not receive it were not at an elevated risk of breast cancer-specific mortality ( Table 2 ) ( Figure 3 ). However, when tumor characteristics were compared by chemotherapy receipt, the women who did not receive chemotherapy had more favorable prognostic indicators: a smaller tumor size (≤ 2 cm vs. larger, p=.01) and a greater proportion of negative nodes (p=.009). By contrast, the women who met the guidelines for radiotherapy but did not receive it had a 2.3-fold increased risk of breast cancer-specific mortality compared to those who received treatment ( Figure 4 ), and that risk remained elevated more than 2-fold among those who survived 24 months. Similarly, the women who were eligible for endocrine therapy but did not receive it had 2.0-fold increased mortality relative to the treated women ( Figure 5 ), with a similar mortality increase among those with 24 months or greater survival. Lack of receipt of guideline-concordant radiation and endocrine therapy independently contributed to statistical models of breast cancer survival, after adjustment for other prognostic indicators ( Table 3 ).

Breast cancer-specific survival according to receipt of chemotherapy among invasive breast cancer cases eligible for such treatment by the National Comprehensive Cancer Network (NCCN) guidelines

Breast cancer-specific survival according to receipt of radiotherapy among invasive breast cancer cases eligible for such treatment by the National Comprehensive Cancer Network (NCCN) guidelines

Breast cancer-specific survival according to receipt of endocrine therapy among invasive breast cancer cases eligible for such treatment by the National Comprehensive Cancer Network (NCCN) guidelines

Treatment initiation and breast cancer-specific mortality among incident invasive breast cancer cases for whom therapy was indicated by the National Comprehensive Cancer Network (NCCN) guidelines. Restricted to women who survived 12 or more months or 24 or more months.

Contribution of guideline-discordant treatment to breast cancer-specific mortality.

We evaluated whether Hispanic women were less likely to receive guideline-appropriate therapy, which could plausibly influence breast cancer survival disparities. Contraindications for chemotherapy differed by ethnicity (19.7% in Hispanics vs. 29.3% in non-Hispanic whites; p=.04), whereas the contraindications for radiotherapy (6.0% vs. 4.7%) or endocrine therapy (20.6% vs. 14.0%) did not ( Table 4 ). Hispanic women were slightly more likely than non-Hispanic white women to receive chemotherapy (84.2% vs. 81.3%, respectively) and endocrine therapy (89.2% vs. 85.8%, respectively) and were almost equally likely to receive radiation therapy (89.2% vs. 91.1%, respectively). Thus, treatment did not differ significantly by ethnicity. We next examined whether the Hispanic survival HR was altered by adjustment for variables indicating guideline-consistent treatment in Cox regression models, which would suggest that treatment receipt influenced disparities. Adjustment for each therapy did not materially alter the Hispanic survival disparity HR. In separate Cox multivariate models restricted to those guideline-eligible for each treatment, the interaction terms between Hispanic ethnicity and each treatment were non-significant, implying that the effect of treatment did not differ by ethnic group and that the Hispanic survival disparity did not differ by treatment. Hispanic women remained at an increased risk of breast cancer-related mortality in each stratum restricted to those who received guideline-appropriate therapy ( Table 4 ).

Stratified analysis of treatment initiation and breast cancer-specific mortality according to Hispanic ethnicity among incident invasive breast cancer cases for whom treatment was indicated by the National Comprehensive Cancer Network (NCCN) guidelines.

Abbreviations: NCCN – National Comprehensive Cancer Network

We examined breast cancer survival disparities by ethnicity in a large population-based study of women diagnosed with breast cancer between 1997 and 2009 who were followed for a median of 8.4 years. We evaluated the treatment received using detailed information abstracted from medical records and applied NCCN-guideline criteria specific to diagnosis year to evaluate appropriate treatment. Our results suggest that women had a 2.0- to 2.3-fold elevated risk of breast cancer-related death if they did not receive guideline-consistent radiotherapy or endocrine therapy, implying that guideline-concordant therapy has a substantial influence on prognosis. Because Hispanic women were equally as likely to receive NCCN guideline-appropriate therapy as non-Hispanic white women, and because adjustment for treatment did not alter the Hispanic HR, treatment was not identified as a determinant of survival disparities.

Our results should be interpreted in light of the strengths and limitations of this study. We could not thoroughly evaluate therapy completion in all women; thus, only the initial receipt of guideline-consistent therapy was assessed. Additionally, although we reviewed both inpatient and outpatient medical charts and electronic and paper records to ascertain therapy, some forms of therapy may have been under-ascertained. Treatment determined using medical records, which frequently included dates of initiation, doses, and agents, is less likely to be over-ascertained. SEER information, which was utilized for a small proportion of the included women, also has a high positive predictive value for therapy[ 18 ]. The restriction of included women to those aged less than 70 years diagnosed with stage I–III disease who survived at least 12 months post-diagnosis provided a solid foundation to evaluate treatment receipt only among women who survived a sufficient time to initiate therapy and who were less likely than older women to omit treatment[ 28 ], including for comorbidities[ 16 ]. Other strengths of our study include the population-based case-cohort design, extensive detailed data collection, and the length of follow-up.

Our study is one of very few[ 4 , 6 ] to quantify the distinct survival disadvantages accrued by women who do not receive guideline-recommended care. Women who did not receive indicated endocrine therapy or radiotherapy had a 2.0- to 2.3-fold elevated risk of breast cancer mortality, independent of other risk factors for outcome. The likelihood ratio test ( Table 3 ) suggests a contribution similar to that of other important prognostic indicators[ 29 ].

Our study results are consistent with those of other investigations that suggest that treatment accounts for little if any difference in breast cancer outcomes by race or ethnicity [ 13 , 30 – 33 ], but they are inconsistent with other studies. In randomized clinical trials, survival disparities by race have persisted despite equal treatment[ 30 , 31 , 33 ]. Among women with equal access to care through the Department of Defense or Medicare, breast cancer survival disparities continue [ 34 ], although not in early stage disease [ 35 ], and treatment accounted for only a limited proportion of racial differences in all-cause mortality [ 32 ]. However, Hispanic (or Black) women have been less likely to receive guideline-consistent treatment in several studies [ 7 , 9 ]. By contrast, in medical record data obtained for a population-based sample of SEER breast cancer cases, which allowed treatment evaluation beyond the initial first course usually available in SEER [ 17 , 18 ], Hispanic women were slightly more likely than non-Hispanic whites to receive guideline-concordant chemotherapy and radiotherapy, but not endocrine therapy[ 28 ]. In two additional studies that utilized self-report and medical record or SEER data, Hispanic or Black women were equally as likely to receive chemotherapy[ 36 ] or radiotherapy[ 37 ] as non-Hispanic white women. The proportion of women who received guideline-concordant therapy in our investigation was consistent with that reported in the latter three investigations[ 28 , 36 , 37 ].

In our population-based study in New Mexico, a state with the nation’s second highest uninsured rate during the included years[ 38 ], the proportion of women who received guideline-concordant care was high (>85% for non-chemotherapy), suggesting that clinicians and patients strongly adhere to quality of care recommendations and providing assurance that disparate survival in this setting is not arising from gaps in care. The increased risk of breast cancer-related deaths persisted even among Hispanic women who received full guideline-concordant treatment. Thus, equalizing receipt of standard of care and attempting to reduce treatment disparities may not be sufficient to address the disproportionate mortality evident in Hispanic women with breast cancer.

Acknowledgments

Funding information:

This study was supported by grants R01CA132877 and 2P30CA11810 from the National Cancer Institute (NCI) and NCI contract HSN26120130010I-Task Order HHSN26100005 to the Surveillance Epidemiology End Results (SEER) program.

We would like to thank Ms. Kimberly Cooke, Mr. Nicolas Eldredge, Ms. Rebecca Sando, Ms. Chanel Jim, Mr. Francisco Martinez, Ms. Nancy Brito, and Ms. Georgia Hufnagel for their assistance in conducting this study.

Conflict of interest information:

The authors declare that they do not have a conflict of interest in connection with this manuscript.

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Share and Cite

Kawiak, A. Molecular Research and Treatment of Breast Cancer. Int. J. Mol. Sci. 2022 , 23 , 9617. https://doi.org/10.3390/ijms23179617

Kawiak A. Molecular Research and Treatment of Breast Cancer. International Journal of Molecular Sciences . 2022; 23(17):9617. https://doi.org/10.3390/ijms23179617

Kawiak, Anna. 2022. "Molecular Research and Treatment of Breast Cancer" International Journal of Molecular Sciences 23, no. 17: 9617. https://doi.org/10.3390/ijms23179617

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BRCA Gene Mutations: Cancer Risk and Genetic Testing

What are brca1 and brca2 .

BRCA1 (BReast CAncer gene 1) and BRCA2 (BReast CAncer gene 2) are genes that produce proteins that help repair damaged DNA. Everyone has two copies of each of these genes—one copy inherited from each parent. BRCA1 and BRCA2 are sometimes called tumor suppressor genes because when they have certain changes, called harmful (or pathogenic) variants (or mutations ), cancer can develop.

People who inherit harmful variants in one of these genes have increased risks of several cancers—most notably breast and ovarian cancer, but also several additional types of cancer. People who have inherited a harmful variant in BRCA1 and BRCA2 also tend to develop cancer at younger ages than people who do not have such a variant. 

A harmful variant in BRCA1 or BRCA2 can be inherited from either parent. Each child of a parent who carries any mutation in one of these genes has a 50% chance (or 1 in 2 chance) of inheriting the mutation. Inherited mutations—also called germline mutations  or variants—are present from birth in all cells in the body.  

Even if someone has inherited a harmful variant in BRCA1 or BRCA2 from one parent, they would have inherited a normal copy of that gene from the other parent (that’s because in most cases, embryos with a harmful variant from each parent cannot develop). But the normal copy can be lost or change in some cells in the body during that person’s lifetime. Such a change is called a somatic alteration . Cells that don’t have any functioning BRCA1 or BRCA2 proteins can grow out of control and become cancer.

How much does an inherited harmful variant in BRCA1 or BRCA2 increase a woman’s risk of breast and ovarian cancer?

A woman’s lifetime risk of developing breast  and/or ovarian cancer is markedly increased if she inherits a harmful variant in BRCA1 or BRCA2 , but the degree of increase varies depending on the mutation.

Breast cancer :  About 13% of women in the general population will develop breast cancer sometime during their lives ( 1 ). By contrast, 55% – 72% of women who inherit a harmful BRCA1 variant and 45% – 69% of women who inherit a harmful BRCA2 variant will develop breast cancer by 70–80 years of age ( 2 – 4 ). The risk for any one woman depends on a number of factors, some of which have not been fully characterized. 

Like women with breast cancer in general, those with harmful BRCA1 or BRCA2 variants also have an increased risk of developing cancer in the opposite ( contralateral ) breast in the years following a breast cancer diagnosis  ( 2 ). The risk of contralateral breast cancer increases with the time since a first breast cancer, reaching 20%–30% at 10 years of follow-up and 40%–50% at 20 years, depending on the gene involved.

Ovarian cancer: About 1.2% of women in the general population will develop ovarian cancer sometime during their lives ( 1 ). By contrast, 39%–44% of women who inherit a harmful BRCA1 variant and 11%–17% of women who inherit a harmful BRCA2 variant will develop ovarian cancer by 70–80 years of age ( 2 – 4 ).

What other cancers are linked to harmful variants in BRCA1 and BRCA2 ?

Harmful variants in BRCA1 and BRCA2 increase the risk of several additional cancers. In women, these include fallopian tube cancer ( 5 , 6 ) and primary peritoneal cancer ( 7 ), both of which start in the same cells as the most common type of ovarian cancer. Men with BRCA2 variants, and to a lesser extent BRCA1 variants, are also at increased risk of breast cancer ( 8 ) and prostate cancer ( 9 – 11 ). Both men and women with harmful BRCA1 or BRCA2 variants are at increased risk of pancreatic cancer , although the risk increase is low ( 12 – 14 ).

In addition, certain variants in BRCA1 and BRCA2 can cause subtypes of Fanconi anemia , a rare syndrome that is associated with childhood solid tumors and development of acute myeloid leukemia ( 15 – 17 ). The mutations that cause these Fanconi anemia subtypes have a milder effect on protein function than the mutations that cause breast and ovarian cancer. Children who inherit one of these variants from each parent will develop Fanconi anemia.  

Are harmful variants in BRCA1 and BRCA2 more common in certain racial/ethnic populations than others?

Yes. The likelihood of carrying an inherited mutation in BRCA1 or BRCA2 (the prevalence ) varies across specific population groups. While the prevalence in the general population is about 0.2%–0.3% (or about 1 in 400), about 2.0% of people of Ashkenazi Jewish  descent carry a harmful variant in one of these two genes and the variants are usually one of three specific variants, called founder mutations. Other populations, such as Norwegian, Dutch, and Icelandic peoples, also have founder mutations ( 18 ).

Different racial/ethnic and geographic populations also tend to carry different variants in these genes. For instance, African Americans have BRCA1 variants that are not seen in other racial/ethnic groups in the United States ( 19 – 21 ). Most people of Ashkenazi Jewish descent in the United States who carry a BRCA variant have one of three specific variants (two in BRCA1 and one in BRCA2 ). In the Icelandic population, a different variant in BRCA1 is common among those who inherit a mutation in BRCA1 . 

Who should consider genetic counseling and testing for BRCA1 and BRCA2 variants?

Anyone who is concerned about the possibility that they may have a harmful variant in the BRCA1 or BRCA2 gene should discuss their concerns with their health care provider or a genetic counselor .

Tests are available to see if someone has inherited a harmful variant in BRCA1 and BRCA2 . However, testing is not currently recommended for the general public. Instead, expert groups recommend that testing be focused on those who have a higher likelihood of carrying a harmful BRCA1 or BRCA2 variant, such as those who have a family history of certain cancers. Testing can be appropriate for both people without cancer as well as people who have been diagnosed with cancer. If someone knows they have a mutation in one of these genes, they can take steps to reduce their risk or detect cancer early. And if they have cancer, the information about their mutation may be important for selecting treatment. 

Before testing is done, a person will usually have a risk assessment , in which they meet with a genetic counselor or other health care provider to review factors such as which of their relatives had cancer, what cancers they had, and at what ages they were diagnosed. If this assessment suggests that someone has an increased risk of carrying a harmful BRCA1 or BRCA2 gene variant, their genetic counselor can discuss the benefits and harms of testing with them and order the appropriate genetic test, if the individual decides to have genetic testing ( 22 ). 

Some people may choose to have genetic testing via direct-to-consumer (DTC) testing . Genetic counseling is recommended for those people as well to help them understand the test results and to make sure the most appropriate test was done. People should be aware that DTC tests may not be comprehensive, in that some tests do not test for all of the harmful mutations in the two genes. So receiving a negative result with a DTC test may not mean that they don’t have a harmful variant in BRCA1 or BRCA2 .

The United States Preventive Services Task Force recommends risk assessment for women who have a personal or family history of breast , ovarian , fallopian tube , or peritoneal cancer or whose ancestry is associated with having harmful BRCA1 and BRCA2 variants, as well as follow-up genetic counseling as appropriate.    The National Comprehensive Cancer Network (NCCN) has criteria for genetic testing of BRCA1 and BRCA2 as well as for several other genes (including CDH1 , PALB2 , PTEN , and TP53 ) that are associated with increased risk of breast and/or ovarian cancer ( 23 ). NCCN recommends risk assessment for people who have a blood relative with a known or likely harmful variant in any of these genes; who have certain personal and/or family histories of cancer (cancer diagnosed at a younger age, certain types of cancer, people with two or more cancer diagnoses, or families with multiple cases of cancer); or who have certain inherited cancer predisposition disorders, such as Cowden syndrome , Peutz-Jeghers syndrome , Li-Fraumeni syndrome , or Fanconi anemia . 

The American Society of Clinical Oncology recommends that all women diagnosed with epithelial ovarian cancer be offered genetic testing for inherited variants in BRCA1 , BRCA2 , and other ovarian cancer susceptibility genes, regardless of the clinical features of their disease or their family history ( 24 ).

Professional societies do not recommend that children under age 18 undergo genetic testing for BRCA1 and BRCA2 variants. This is because there are no risk-reduction strategies that are specifically meant for children, and children are very unlikely to develop a cancer related to an inherited BRCA variant. 

Testing for inherited BRCA1 and BRCA2 variants may be done using a blood sample or a saliva sample. That is because blood cells and cells that are present in saliva, like every cell in the body, contain the BRCA1 and BRCA2 genes. Sometimes people with cancer find out that they have a BRCA1 or BRCA2 mutation when their tumor is tested to see if they are a candidate for treatment with a particular targeted therapy . Because harmful BRCA variants reported in the tumor may be of somatic  or germline  origin, someone with such a variant in their tumor should consider having a germline genetic (blood) test to determine if the variant was inherited. 

When a family history suggests the possibility that someone without cancer may have inherited a harmful variant in BRCA1 or BRCA2 , it is best for a family member who has already been diagnosed with cancer to be tested, if such a person is alive and willing to get tested. If such testing reveals a known harmful variant, then testing the individual for that variant will provide a clear indication of whether they also carry it. If all family members with cancer are deceased or are unwilling or unable to have genetic testing, testing family members who have not been diagnosed with cancer may still be of value and provide good information. 

Does health insurance cover the cost of genetic testing for BRCA1 and BRCA2 variants?

People considering BRCA1 and BRCA2 variant testing may want to confirm their insurance coverage for genetic counseling and testing. Genetic counselors can often help answer questions about insurance coverage for genetic testing .

Some genetic testing companies may offer testing for inherited BRCA1 and BRCA2 variants at no charge to patients who lack insurance and meet specific financial and medical criteria.

What do BRCA1 and BRCA2 genetic test results mean?

BRCA1 and BRCA2 mutation testing can give several possible results: a positive result, a negative result, or a variant of uncertain significance (VUS) result.

Positive result. A positive test result indicates that a person has inherited a known harmful variant in BRCA1 or BRCA2 (these are typically called “pathogenic” or “likely pathogenic” variants on laboratory test reports) and has an increased risk of developing certain cancers. However, a positive test result cannot tell whether or when the tested individual will develop cancer. Some people who inherit a harmful BRCA1 or BRCA2 variant never develop cancer.

A positive test result may also have important implications for family members, including future generations.

• Both men and women who inherit a harmful BRCA1 or BRCA2 variant, whether or not they develop cancer themselves, may pass the variant to their children. Each child has a 50% chance of inheriting a parent’s variant.
• All blood relatives of a person who has inherited a harmful BRCA1 or BRCA2 variant are at some increased risk of having the variant themselves. For example, each of that person’s full siblings has a 50% chance of having inherited the variant as well.
• Very rarely, an individual may test positive for a harmful variant not inherited from either parent. This is called a de novo (or “new”) variant. Such a variant is one that arose in a germ cell (sperm or egg) of one of the parents and is present in all the cells of the person who grew from that cell. The children of someone with a de novo variant (but not his or her siblings) are at risk of inheriting the variant.

Negative result. A negative test result can have several meanings, depending on the personal and family medical history of the person who is tested and whether or not a harmful mutation has already been identified in the family. If a close blood relative of the tested person is known to carry a harmful BRCA1 or BRCA2 variant, a negative test result is clear: it means the tested person did not inherit the harmful variant that is present in the family and cannot pass it to their children. A person with such a test result, called a true negative, has a risk of cancer that is similar to that of someone in the general population. However, there are other factors besides genetic factors that may increase the risk of cancer, such as radiation exposures at an early age, and those factors should be considered in assessing their risk of cancer. 

If the tested person has no personal history of cancer and their family isn’t known to carry a harmful variant, then in this case, a negative test result is considered to be “uninformative.” There are several possible reasons why someone could have an uninformative negative test result:

• Without testing family members who have had cancer, it is uncertain whether the negative test means that the person did not inherit a BRCA1 or BRCA2 mutation that is present in the family or whether the family history might be due to a mutation in another gene that was not tested or to other, nongenetic  risk factors .
• The individual may have a harmful variant that is not detectable by current testing technologies.
• Rarely, there could be an error in the testing, either because inappropriate tests were recommended or ordered, genetic variants were interpreted incorrectly, or the wrong results were relayed to patients ( 25 ).

Variant of Uncertain Significance (VUS) result. Sometimes, a genetic test finds a change in BRCA1 or BRCA2 that has not been previously associated with cancer and is uncommon in the general population. This type of test result is called “a variant of uncertain significance,” or VUS, because it isn’t known whether this specific genetic change is harmful.   

As more research is conducted and more people are tested for BRCA1 and BRCA2 variants, scientists will learn more about uncertain changes and cancer risk. Clinicians and scientists are actively working to share information on these mutations so that they can be reclassified as either clearly harmful or clearly not harmful ( 26 , 27 ). 

Genetic counseling can help a person understand what a VUS in BRCA1 or BRCA2 may mean in terms of their cancer risk. Until the interpretation of the variant is clarified, management of risk should be based on family history and other risk factors. However, it is important that a person who has a VUS test result regularly obtains updated information from the testing provider in case that VUS is reclassified as a harmful or likely harmful variant. Testing providers have different policies about notifying a tested person of a change in the interpretation of a VUS test result. Some will contact the tested person directly, whereas others place the responsibility on the tested person to check back in on a regular basis to learn of updates to the interpretation of their VUS test result. 

How can a person who has inherited a harmful BRCA1 or BRCA2 gene variant reduce their risk of cancer?

Several options are available for reducing cancer risk in individuals who have inherited a harmful BRCA1 or BRCA2 variant. These include enhanced screening , risk-reducing surgery  (sometimes referred to as prophylactic surgery), and chemoprevention .

Enhanced screening. Some women who test positive for harmful BRCA1 and BRCA2 variants may choose to start breast cancer screening at younger ages, have more frequent screening than is recommended for women with an average risk of breast cancer, or have screening with magnetic resonance imaging (MRI) in addition to mammography . 

No effective ovarian cancer screening methods are known. Some groups recommend transvaginal ultrasound , blood tests for the CA-125 antigen (which can be present at higher-than-normal levels in women with ovarian cancer), and clinical examinations for ovarian cancer screening in women with harmful BRCA1 or BRCA2 variants. However, none of these methods appear to detect ovarian tumors at an early enough stage to improve long-term survival ( 28 ). 

The benefits of screening men who carry harmful variants in BRCA1 or BRCA2 for breast and other cancers are not known. Some expert groups recommend that such men undergo regular annual clinical breast exams starting at age 35 ( 23 ). The National Comprehensive Cancer Network (NCCN) guidelines recommend that men with harmful germline variants in BRCA1 or BRCA2 consider having a discussion with their doctor about prostate-specific antigen (PSA) testing for prostate cancer screening starting at age 40 ( 29 ).

Some experts recommend the use of ultrasound or MRI/magnetic retrograde cholangiopancreatography to screen for pancreatic cancer in people who are known to carry a harmful BRCA1 or BRCA2 variant and who have a close blood relative with pancreatic cancer ( 30 ). However, it is not yet clear whether pancreatic cancer screening and early pancreatic cancer detection reduces the overall risk of dying from a pancreatic cancer. 

All of these screening approaches have potential harms as well as possible benefits. For example, MRI is more likely than mammography to result in false-positive findings. And there is some concern that women who have a harmful BRCA variant might be particularly sensitive to the DNA-damaging effects of tests that involve radiation (such as mammography) because they already have a defect in DNA repair ( 31 ). 

Risk-reducing surgery. Risk-reducing, or prophylactic, surgery involves removing as much of the "at-risk" tissue as possible. Women may choose to have both breasts removed ( bilateral risk-reducing mastectomy ) to reduce their risk of breast cancer. Surgery to remove a woman's ovaries and fallopian tubes ( bilateral risk-reducing salpingo-oophorectomy ) can help reduce her risk of ovarian cancer. ( Ovarian cancers often originate in the fallopian tubes, so it is essential that they be removed along with the ovaries.) Removing the ovaries may also reduce the risk of breast cancer in premenopausal women by eliminating a source of hormones that can fuel the growth of some types of breast cancer. 

These surgeries are irreversible, and each has potential complications or harms . These include bleeding or infection, anxiety and concerns about body image (bilateral risk-reducing mastectomy), and early menopause in premenopausal women (bilateral risk-reducing salpingo-oophorectomy).

Risk-reducing surgery does not guarantee that cancer will not develop because not all at-risk tissue can be removed by these procedures. That is why these surgical procedures are described as “risk-reducing” rather than “preventive.” Some women have developed breast cancer, ovarian cancer, or primary peritoneal carcinomatosis (a type of cancer similar to ovarian cancer) even after risk-reducing surgery. Nevertheless, these surgical procedures greatly reduce risk. For example, in several studies women who underwent bilateral salpingo-oophorectomy had a nearly 80% reduction in risk of dying from ovarian cancer, a 56% reduction in risk of dying from breast cancer ( 32 ), and a 77% reduction in risk of dying from any cause during the studies’ follow-up periods ( 33 ).

The reduction in breast and ovarian cancer risk from removal of the ovaries and fallopian tubes appears to be similar for carriers of BRCA1 and BRCA2 variants ( 33 ).

Chemoprevention. Chemoprevention is the use of medicines to reduce the risk of cancer. Two chemopreventive drugs ( tamoxifen [Nolvadex]  and raloxifene [Evista] ) have been approved by the Food and Drug Administration (FDA) to reduce the risk of breast cancer in women at increased risk , but the role of these drugs in women with harmful BRCA1 or BRCA2 variants is not yet clear. Data from three studies suggest that tamoxifen may be able to help lower the risk of breast cancer in women who carry harmful variants in BRCA2 ( 34 ) and of cancer in the opposite breast among BRCA1 and BRCA2 variant carriers previously diagnosed with breast cancer ( 35 , 36 ). Studies have not examined the effectiveness of raloxifene in BRCA1 and BRCA2 variant carriers specifically. 

However, these medications may be an option for women who choose not to, or who cannot, undergo surgery. The potential harms of these drugs include menopausal symptoms, blood clots , stroke , increased risk of endometrial cancer (tamoxifen), and allergic reactions (raloxifene).

Both women in the general population, as well as those with harmful BRCA1 or BRCA2 variants, who have ever used oral contraceptives (birth control pills)  have about a 50% lower risk of ovarian cancer than women who have never used oral contraceptives ( 37 ). Potential harms of oral contraceptives include increased risk of breast cancer, increased risk that a human papillomavirus (HPV) infection will become cervical cancer , and possible cardiovascular effects among older reproductive-age women.

What are the benefits of genetic testing for BRCA1 and BRCA2 variants?

There can be benefits to genetic testing, regardless of whether a person receives a positive or a negative result.

The potential benefits of a true negative result include a sense of relief regarding the future risk of cancer, learning that one's children are not at risk of inheriting the family's cancer susceptibility, and the possibility that special check-ups, tests, or risk-reducing surgeries may not be needed.

A positive test result may allow people to make informed decisions about their future health care, including taking steps to reduce their cancer risk. 

What are the possible harms of genetic testing for BRCA1 and BRCA2 variants?

The direct medical harms of genetic testing are minimal, but knowledge of test results, whether positive or negative, may have harmful effects on a person’s emotions, social relationships, finances, and medical choices. 

Dealing with uncertainty of an uninformative negative or a VUS test result is another potential harm. For this reason, it is important to have genetic counseling before undergoing genetic testing.

Results of genetic tests are normally included in a person’s medical records, particularly if a doctor or other health care provider has ordered the test or has been consulted about the test results. Therefore, people considering genetic testing must understand that their results may become known to other people or organizations that have legitimate, legal access to their medical records, such as their insurance company or employer, if their employer provides the patient’s health insurance as a benefit.

What are the treatment implications of having a harmful BRCA1 or BRCA2 variant for patients who have already developed cancer?

Because the BRCA1 and BRCA2 genes are involved in DNA repair, tumors with alterations in either gene are particularly sensitive to anticancer agents that act by damaging DNA, such as cisplatin ( 38 ). 

A class of drugs called PARP inhibitors , which block the repair of DNA damage, have been found to arrest the growth of cancer cells that have harmful BRCA1 or BRCA2 variants. Four PARP inhibitors— olaparib [Lynparza] , rucaparib [Rubraca] , niraparib [Zejula] , and talazoparib [Talzenna] —are approved by the FDA to treat certain cancers bearing harmful variants in BRCA1 or BRCA2 . (In some cases, these are used whether or not a BRCA1 or BRCA2 mutation is present.) 

Breast cancers with harmful BRCA1 variants are more likely to be "triple-negative cancers"  (that is, the breast cancer cells do not have estrogen receptors , progesterone receptors , or large amounts of HER2/neu protein ) than sporadic breast cancers  or breast cancers with harmful BRCA2 variants. Triple-negative cancers are harder to treat and have a poorer prognosis than other types of breast cancers.

If someone has tumor genetic testing that reveals the presence of a harmful BRCA1 or BRCA2 variant in the tumor, they should consider having a germline genetic (blood) test to determine if the variant was inherited. Knowing if the variant was inherited is important for that individual to understand their risks to potentially develop other cancers in the future. It can also determine if other family members may be at risk of inheriting the harmful variant.

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Breast cancer chemoprevention: drugs that reduce risk.

Preventive medications can reduce breast cancer risk. Learn about how these drugs work, who should consider taking them, plus their side effects and health risks.

If you're at high risk of breast cancer, you may be able to improve your odds of staying cancer-free by taking certain medicines — an approach known as chemoprevention or preventive therapy.

Medications for breast cancer chemoprevention are the subject of much ongoing research.

Here's a look at what's known about each of these medications, including how they may work to prevent breast cancer and the possible side effects and health risks.

How it works

Tamoxifen blocks the effects of estrogen — a reproductive hormone that influences the growth and development of many breast cancers.

Tamoxifen belongs to a class of drugs known as selective estrogen receptor modulators (SERMs). The drug reduces the effects of estrogen in most areas of the body, including the breast. In the uterus, however, tamoxifen acts like an estrogen and encourages the growth of the lining of the uterus.

Tamoxifen is usually prescribed as a pill taken once a day by mouth. For breast cancer risk reduction, tamoxifen is typically taken for a total of five years. The risk reduction benefit continues for five additional years after you stop taking tamoxifen. In total, you could receive up to 10 years of benefit.

Who it's for

Tamoxifen is used to reduce the risk of invasive breast cancer if you're at high risk and you're 35 and older, whether or not you've gone through menopause.

You and your health care provider might consider whether chemoprevention with tamoxifen is right for you if:

• Your Gail model risk score is greater than 1.7%. The Gail model is a tool that health care providers use to predict future risk of developing breast cancer. The risk score is based on factors such as age, reproductive history and family history.
• You're at high risk of developing breast cancer. For instance, you've had a breast biopsy that found a precancerous condition such as lobular carcinoma in situ, atypical ductal hyperplasia or atypical lobular hyperplasia.
• You have a strong family history of breast cancer.
• You don't have a history of blood clots.

Common side effects

Common side effects of tamoxifen include:

• Hot flashes
• Night sweats
• Vaginal discharge
• Vaginal dryness

Rarely, taking tamoxifen may cause:

• Blood clots
• Endometrial cancer or uterine cancer

If you haven't undergone menopause, the risk of uterine cancer when taking tamoxifen is very low compared with the risk for those who have already undergone menopause. In this situation, the benefits of tamoxifen may outweigh the risks if you have an increased risk of breast cancer due to a strong family history or a personal history of precancerous breast changes.

If you've undergone menopause, the benefits of tamoxifen may outweigh the risks if you have an increased risk of breast cancer and have also had surgery to remove your uterus (hysterectomy).

Raloxifene (Evista) is another drug in the class known as SERMs. It's also prescribed in pill form, to be taken by mouth once a day for five years.

Like tamoxifen, raloxifene works by blocking estrogen's effects in the breast and other tissues. Unlike tamoxifen, raloxifene doesn't exert estrogen-like effects on the uterus.

Raloxifene is used to reduce the risk of invasive breast cancer if you're at high risk and you've undergone menopause (postmenopausal). You're considered at high risk if you score greater than 1.7% on the Gail model.

Raloxifene is also used for prevention and treatment of the bone-thinning disease osteoporosis in those who've undergone menopause.

Common side effects of raloxifene include:

• Vaginal dryness or irritation
• Joint and muscle pain
• Weight gain

Health risks associated with raloxifene are similar to those associated with tamoxifen.

Both drugs carry an increased risk of blood clots, though the risk may be lower with raloxifene. Raloxifene may be associated with fewer instances of endometrial and uterine cancers than is tamoxifen.

Raloxifene may also be linked to fewer strokes than tamoxifen in people at average risk of heart disease. But if you have heart disease or you have multiple risk factors for heart disease, raloxifene may increase your risk of strokes.

Although tamoxifen may be slightly better than raloxifene at reducing the risk of breast cancer, the risk of blood clots and uterine cancer are lower with raloxifene. For this reason, raloxifene may be a preferred option if you've undergone menopause and haven't had a hysterectomy or have osteoporosis.

Aromatase inhibitors

Aromatase inhibitors are commonly used to treat breast cancer that's hormone receptor positive. These drugs are also an option for breast cancer chemoprevention.

How they work

Aromatase inhibitors are a class of medicines that reduce the amount of estrogen in your body, depriving breast cancer cells of the fuel they need to grow and thrive.

Three aromatase inhibitors are currently approved in the United States for breast cancer treatment: anastrozole (Arimidex), exemestane (Aromasin) and letrozole (Femara).

These medications are used to treat breast cancer that's estrogen- or progesterone-responsive in those who've undergone menopause.

Who they're for

Aromatase inhibitors have been studied and shown to be effective to treat breast cancer and to prevent breast cancer recurrence after menopause. Aromatase inhibitors are not intended for preventing breast cancer recurrence if you still have menstrual cycles.

Aromatase inhibitors, specifically exemestane and anastrozole, have also been studied to see if they may reduce the risk of breast cancer in people at high risk, such as those with a family history of breast cancer or a history of precancerous breast lesions. Studies have shown promise in reducing breast cancer risk in these individuals.

Based on these results, you and your health care provider may choose to use aromatase inhibitors to reduce the risk of breast cancer, though these drugs aren't approved by the U.S. Food and Drug Administration for this use.

Additional studies are underway to determine whether aromatase inhibitors may reduce the risk of breast cancer in those with genetic mutations that increase the risk of breast cancer.

Common side effects of aromatase inhibitors include:

Aromatase inhibitors increase the risk of osteoporosis.

Aromatase inhibitors aren't associated with an increased risk of blood clots or uterine cancer, as tamoxifen and raloxifene are. Because aromatase inhibitors are a newer class of medications, more research needs to be done about long-term health risks, such as heart disease and broken bones.

As more results from research studies become available, health care providers will have a better idea of the long-term health implications for these drugs and their effectiveness in breast cancer chemoprevention.

• Breast cancer risk reduction. National Comprehensive Cancer Network. https://www.nccn.org/guidelines/guidelines-detail?category=2&id=1420. Accessed Sept. 13, 2021.
• Visvanathan K, et al. Use of endocrine therapy for breast cancer risk reduction: ASCO clinical practice guideline update. Journal of Clinical Oncology. 2019; doi:10.1200/JCO.19.01472.
• Owens DK, et al. Medication use to reduce risk of breast cancer: US Preventive Services Task Force recommendation statement. JAMA. 2019; doi:10.1001/jama.2019.11885.
• Lee B, et al. Prevalence, incidence and risk factors of tamoxifen-related non-alcoholic fatty liver disease: A systematic review and meta-analysis. Liver International. 2020; doi:10.1111/liv.14434.
• Sharma P. Selective estrogen receptor modulators and aromatase inhibitors for breast cancer prevention. https://www.uptodate.com/contents/search. Accessed Sept. 9, 2021.
• Bland KI, et al., eds. Primary prevention of breast cancer. In: The Breast: Comprehensive Management of Benign and Malignant Diseases. 5th ed. Elsevier; 2018. https://www.clinicalkey.com. Accessed July 1, 2021.
• Lee Y-S, et al. Underlying nonalcoholic fatty liver disease is a significant factor for breast cancer recurrence after curative surgery. Medicine. 2019; doi:10.1097/MD.0000000000017277.
• Breast cancer prevention (PDQ) — Health professional version. National Cancer Institute. https://www.cancer.gov/types/breast/hp/breast-prevention-pdq. Accessed Sept. 12, 2021.
• Hyder T, et al. Aromatase inhibitor-associated musculoskeletal syndrome: Understanding mechanisms and management. Frontiers in Endocrinology. 2021; doi:10.3389/fendo.2021.713700.
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• Published: 18 June 2024

Measurement properties of the Iranian version of the breast cancer perception scale (BCPS) according to the COSMIN checklist

• Sepideh Mashayekh-Amiri 1 ,
• Mohammad Asghari Jafarabadi 2 , 3 , 4 ,
• Mina Hosseinzadeh 5 ,
• Elham seyed Kanani 6 &
• Mojgan Mirghafourvand 7 , 8  

BMC Cancer volume  24 , Article number:  743 ( 2024 ) Cite this article

Metrics details

Breast cancer is a prevalent cancer characterized by its aggressive nature and potential to cause mortality among women. The rising mortality rates and women’s inadequate perception of the disease’s severity in developing countries highlight the importance of screening using conventional methods and reliable scales. Since the validity and reliability of the breast cancer perception scale (BCPS) have not been established in the Iranian context. Therefore, this study aimed to determine the measurement properties of the BCPS in women residing in Tabriz, Iran.

The present study comprised a cross-sectional design, encompassing a sample of 372 Iranian women. The participants were selected through a multi-stage cluster random sampling technique conducted over a period spanning from November 2022 to February 2023. The measurement properties of the Iranian version of BCPS were assessed following the guidelines outlined in the COSMIN checklist. This involved conducting various steps, including the translation process, reliability testing (internal consistency, test-retest reliability, and measurement error), and methodological tests for validity (content validity, face validity, construct validity, and hypothesis testing). The study also investigated the factors of responsiveness and interpretability. The presence of floor and ceiling effects was assessed.

The internal consistency of the scale was assessed using Cronbach’s alpha, yielding a satisfactory value of 0.68. Additionally, McDonald’s omega (95% CI) was computed, resulting in a value of 0.70 (0.66 to 0.74). Furthermore, the test-retest reliability was evaluated, revealing a high intraclass correlation coefficient (ICC) of 0.97 (95% CI: 0.94 to 0.99). The CVI, CVR, and impact scores of the BCPS were determined to be 0.98, 0.95, and 3.70, respectively, indicating favorable levels of content and face validity. To assess construct validity, an examination of the Exploratory Factor Analysis (EFA) was conducted on a set of 24 items. This analysis revealed the presence of six distinct factors, which collectively accounted for 52% of the cumulative variance. The fit indices of the validity model (CFI = 0.91, NFI = 0.96, RFI = 0.94, TLI = 0.90, χ 2 /df = 2.03, RMSEA = 0.055 and SRMR = 0.055) were confirmed during the confirmatory factor analysis (CFA). The overall score of BCPS exhibited a ceiling effect of 0.3%. The floor effect observed in the overall score (BCPS) was found to be 0.5%. Concerning the validation of the hypothesis, Spearman’s correlation coefficient of 0.55 was obtained between the BCPS and the QLICP-BR V2.0. This correlation value signifies a statistically significant association. Furthermore, it is worth noting that the minimum important change (MIC) of 3.92 exhibited a higher value compared to the smallest detectable change (SDC) of 3.70, thus suggesting a satisfactory level of response.

Conclusions

The obtained findings suggest that the Iranian version of the BCPS demonstrates satisfactory psychometric properties for assessing the perception of breast cancer among Iranian women. Furthermore, it exhibits favorable responsiveness to clinical variations. Consequently, it can serve as a screening instrument for healthcare professionals to comprehend breast cancer and as a reliable tool in research endeavors.

Peer Review reports

Breast cancer is a significant global health issue [ 1 ], accounting for approximately 30% of cancer cases among women [ 2 ]. It is recognized as the second-leading cause of mortality in developed nations and the third-leading cause of mortality in less developed nations [ 3 ]. Based on the findings of the Global Cancer Incidence, Mortality and Prevalence (GLOBOCAN) report in 2020, it was determined that there were an estimated 2,261,419 million new cases (1 in 4 new cancer cases) (11.7%), and 684,996 (1 in 6 deaths) (6.9%) fatalities [ 4 ]. It is also predicted that these figures will reach 2,964,197 in 2040 (31% rise from 2018) [ 5 ], and 4.4 million in 2070 (110% rise from 2018) [ 6 ]. According to the report of the American Cancer Society in 2024, the number of new cases of female breast cancer in the United States was 310,720 and the number of deaths was 42,250 [ 7 ]. Approximately two-thirds of these fatalities are documented in regions with lower levels of development [ 4 ]. Alternatively, based on the projection provided by the World Health Organization (WHO), it is anticipated that by 2050, approximately 2.3 million women will receive a diagnosis of breast cancer [ 8 ]. Breast cancer is recognized as a highly costly form of cancer on a global scale, with an estimated annual expenditure of approximately 88 billion dollars. Failing to promptly diagnose and conduct screening examinations, coupled with the consequential impact on the entire family unit, imposes substantial financial burdens on society [ 9 ].

Breast cancer exhibits the highest prevalence and mortality rates among women in the Eastern Mediterranean region (EMR), encompassing Iran when compared to other forms of cancer. Breast cancer is widely recognized as the predominant form of cancer in Iran, ranking as the fifth-highest cause of mortality among women in the country [ 10 ]. The Age-standardized rate (ASR) incidence rate is approximately 28 per 100,000 individuals, exhibiting a recent upward trend [ 11 ]. Based on a systematic review, it has been documented that the incidence rate of breast cancer in Iran stands at 23.6% [ 12 ]. The reported prevalence of this cancer in the United States (US) is approximately 13%, indicating that one out of every eight individuals is affected [ 13 ].

Breast cancer is correlated with numerous risk factors, a significant proportion of which remain unidentified. The findings of a systematic review conducted in 2020 in Iran reveal various risk factors associated with breast cancer. These factors include family history, hormone replacement therapy (HRT), exposure to passive smoking, advanced maternal age during pregnancy, history of abortion, consumption of sweets, and possession of the Arg/Arg genotype. These factors have been found to potentially elevate the risk of developing breast cancer. Conversely, certain factors such as the late onset of menstruation, nulliparity, breastfeeding for a duration of 13 to 24 months, regular physical exercise, and consumption of vegetables have been observed to have a protective effect against the incidence of breast cancer [ 14 ].

It is noteworthy that the incidence of breast cancer among Iranian women occurs at an age approximately 10 years earlier compared to women in other developed nations. According to various studies, there has been a documented increase in the prevalence of breast cancer among women under the age of 40 in recent years [ 15 ]. The rise in its occurrence in developing nations is primarily attributed to alterations in lifestyle and reproductive behaviors [ 16 ]. The majority of female individuals afflicted with breast cancer receive a diagnosis during the later stages of the ailment, thereby correlating with an elevated mortality rate. Hence, it has been observed that early detection of breast cancer leads to a significant improvement in both survival rates and treatment outcomes, with a reported increase of 90% [ 17 ].

The United States Office of Disease Prevention and Health Promotion’s Healthy People 2020 initiative has as its goals the improvement of breast cancer diagnostic procedures for women, a decrease in the prevalence of cases of end-stage cancer, and a reduction in breast cancer mortality rates. Conversely, in the case of cancers that exhibit both genetic and environmental risk factors, it is imperative to adopt strategies that prioritize modifiable risk factors and early detection. Hence, the implementation of a preventive strategy aimed at early detection, which incorporates the evaluation of knowledge on breast cancer and its associated risks, assumes paramount significance [ 18 ].

The perception of breast cancer is a crucial subjective psychological phenomenon that is associated with the evaluation of potential threats. This evaluation is linked to an individual’s assessment of their susceptibility to the disease and the probability of gaining advantages from engaging in preventive measures [ 15 ]. Various studies have indicated that risk perception is a significant determinant of preventive health-related behaviors, such as screening. The motivation to undergo screening tests can be influenced by individuals’ perceptions of the risk associated with breast cancer [ 16 ]. According to the literature, screening tests play a crucial role in mitigating complications and mortality associated with breast cancer [ 17 ].

Various studies have documented divergent findings regarding the correlation between the perception of breast cancer risk and the utilization of screening tests, such as mammography [ 18 ]. Research findings indicate that the implementation of mammography screening during the age range of 40 to 49 years has been associated with a reduction in mortality rates of approximately 15 to 20% [ 19 ].

According to a study conducted on families to assess their perception of breast cancer risk, the rate of adherence to screening tests in Germany was found to be 83% [ 20 ]. Conversely, a research study conducted in Iran examined the adherence rate of women aged 35 to 69 years to mammography, as recommended by screening programs. The findings revealed that in urban areas, the adherence rate was 8.3%, while in rural areas, it was 3.16% [ 1 ]. Therefore, the perception level that women possess regarding breast cancer has the potential to influence their subsequent actions, such as seeking medical evaluation and undergoing screening procedures like breast self-examination (BSE), clinical breast examination (CBE), and mammography. Therefore, it is imperative to assess the perception of breast cancer in women using a multidimensional approach [ 20 ].

Numerous methodologies have been suggested for assessing the perception of breast cancer risk, which can be categorized into two distinct types: evaluation of the objective perception of risk (i.e., actual risk) and evaluation of the subjective perception of risk [ 21 ]. Currently, Gill’s model predominantly serves as a tool for conducting quantitative risk assessments. This approach aims to objectively evaluate the actual risk by considering the attributes of risk factors [ 22 ]. The second method entails the assessment of self-perceived risk, which can be anticipated by gauging individuals’ mental perceptions using a visual analog scale (VAS). Despite the presence of a multitude of tools within this domain, their practicality appears to be limited as they do not provide comprehensive coverage of all the factors that influence behaviors related to the diagnosis of breast cancer [ 23 ].

Taylan et al. (2021) developed the BCPS in Turkey, considering the health belief model for the first time. This scale encompasses various domains, including Perceived knowledge, Perceived treatment belief, Perceived need for health check, Perceived stigma, Perceived fear and Perceived risk. The utilization of this scale offers several benefits in assessing women’s perceptions regarding the factors influencing breast cancer diagnostic behavior comprehensively. Furthermore, it is worth noting that the extent of women’s perceived knowledge of breast cancer has not been quantitatively evaluated thus far. Consequently, this tool serves as a distinctive scale specifically designed to measure women’s knowledge regarding cancer. Additionally, it quantifies the dimensions of the breast [ 23 ].

The Health Belief Model (HBM) was initially formulated by Becker et al., in 1974 to comprehend health-related protective behaviors [ 24 ]. The evaluation of perceived risk, employing the HBM, has been validated in various studies examining screening behaviors, such as those related to breast cancer diagnostics [ 25 , 26 , 27 ]. The model encompasses various dimensions, namely perceived sensitivity, perceived severity, perceived benefits, perceived barriers, self-efficacy, and guidance for action. Based on the presented model, individuals’ healthcare behaviors can be subject to influence from factors such as perception, beliefs, values, and attitudes. By identifying and modifying an individual’s perceptions, beliefs, and attitudes, the effectiveness of healthcare education or treatment can be enhanced [ 26 ].

However, it is crucial to assess the methodological rigor of studies that evaluate the measurement properties of instruments used to measure health-related patient-reported outcomes (HR-PROs) [ 28 ]. The Consensus-Based Standards for the Selection of Health Status Measurement Instruments (COSMIN) checklist was developed by Mokkink et al. in 2010 through a consensus-based approach utilizing the Delphi method [ 28 ]. The COSMIN list is widely regarded as a highly comprehensive set of criteria for selecting an appropriate tool. It serves as a valuable guide for researchers, offering a range of logical indicators that aid in the process of tool selection [ 29 ].

Given the rising incidence of breast cancer, the significance of early screening, and the potential influence of risk perception on women’s adoption of preventive behaviors, such as breast screening methods, it is pertinent to assess the level of knowledge regarding breast cancer when devising interventions aimed at modifying health behaviors. It is worth noting that the validity and reliability of the aforementioned assessment tool have not been established in Iran. The present study was undertaken to conduct a measurement propertice of the BCPS in women residing in Tabriz city-Iran, by using the COSMIN checklist.

The present study was conducted with the aim of determining the measurement properties of the breast cancer risk perception scale (BCPS) in according to COSMIN checklist in women in Tabriz, Iran.

Validity procedure

The measurement properties of the Iranian version of BCPS were assessed following the guidelines outlined in the COSMIN checklist [ 29 ]. This involved conducting various steps, including the translation process, reliability testing (internal consistency, test-retest reliability, and measurement error), and methodological tests for validity (content validity, face validity, construct validity, and hypothesis testing). The study also investigated the factors of responsiveness and interpretability. The presence of floor and ceiling effects was assessed.

Translation process

Initially, permission to use the BCPS was obtained by sending an email from the original designer of the instrument (Taylan et al.) [ 23 ]. Efforts were made to maintain the integrity of the original intent during the translation process. Following the recommendations made by the WHO, EORTC Quality of Life Group Translation Procedure Guidelines and expert panel review, this was performed [ 30 ]. The translation process involves the utilization of two distinct methods. The two methods utilized in this study are the Forward-Backward method (FB) and the Dual Panel method (DP), which were implemented throughout four distinct stages. The process consisted of four stages: forward translation, backward translation, pre-testing and cognitive interviewing, and the final version.

During the initial phase of translation, the original English version of the instrument was administered to two individuals who were native Persian speakers, proficient in English, and possessed expertise in the development of the instrument as well as knowledge in the field of breast cancer. Translators were subsequently instructed to translate the tool in a fully autonomous and individual manner, with a focus on conceptual rather than literal translations. Additionally, they were encouraged to use language that would be comprehensible to the majority of the target audience. Ultimately, two translators looked into the discrepancies between the two translated versions, which led to a reconciled translation. Subsequently, the identified issues were addressed, leading to the presentation of a unified version [ 31 ]. Subsequently, the backward translation method was employed to guarantee a comprehensive correspondence between the Persian translation and the original version. The translated questionnaire from the preceding stage was administered to two individuals who are native English speakers. These individuals were not involved in the forward translation process and had no prior exposure to the original version of the questionnaire. They were instructed to retranslate the questionnaire back into English. The concluding report at the culmination of this phase encompassed the following components: two forward translations from the English language to Farsi, a reconciled translation, two backward translations from Farsi to English, and the incorporation of any supplementary remarks regarding the translations provided by the panel of experts. Ultimately, before implementing the tool in the intended population, it is imperative to conduct a pilot study. To achieve the intended objective, a questionnaire was administered to a sample of ten qualified female participants. Based on the feedback received from these participants regarding the ease of completing the instrument, grammar, comprehensibility, and writing style, modifications were made to the Persian version, and the revised version was finalized and presented [ 31 ].

Validation study

This cross-sectional study aimed to assess the measurement properties of the Iranian version of the BCPS among a sample of 372 Iranian women who sought healthcare services at Tabriz health centers affiliated with Tabriz University of Medical Sciences in two separate secondary samples (172 participants via exploratory factor analysis and 200 participants via confirmatory factor analysis). The study was conducted following the approval of the Ethics Committee of Tabriz University of Medical Sciences (ref: IR.TBZMED.REC.1401.390) from November 2022 to February 2023. It is important to acknowledge that informed consent was obtained from all participants. The study was conducted in adherence to the applicable regulations of the Ethics Committee of the University of Medical Sciences and the Declaration of Helsinki.

Among the 410 women, it was found that 16 participants did not satisfy the predetermined eligibility criteria, leading to their exclusion from the research investigation. Out of the remaining 394 participants who met the eligibility criteria, a total of 22 participants expressed their unwillingness to participate in the study. Ultimately, a total of 372 participants were incorporated into the research investigation. The response rate for the study was 94%, (372/394). In the sampling procedure, the cluster method was employed to randomly select a quarter of the 92 health centers in Tabriz City. The selection process was facilitated through the utilization of the website ( www.random.org ). In addition to their contact information, which was obtained from the SIB system (integrated health system), women were selected at random from the compiled list. To clarify, the selection of women from each center was determined based on the proportional sampling method, and the process of randomly selecting women was carried out utilizing the aforementioned website. Following a telephone conversation with the participants, wherein the researcher offered a concise overview of the research, the researcher proceeded to invite the women to attend the designated health center within the specified timeframe. The purpose of this visit was to provide additional explanations and administer the questionnaires. Upon conducting a visit and assessing the fundamental aspects such as basic information and inclusion and exclusion criteria, the individual proceeded to furnish the concerned parties with extensive details related to the research, its advantages, outcomes, and the confidentiality of the data. It is important to acknowledge that the random selection of participants was conducted before the assessment of their eligibility criteria. Following their visit to the health center, participants underwent a comprehensive evaluation to gather baseline data and determine their eligibility. Full information regarding the research objectives and methodology was exclusively provided to individuals who satisfied the predetermined eligibility criteria, and only they were extended an invitation to participatein the study. After agreeing to participate in the study, the participants proceeded to complete the informed consent form, the questionnaire of socio-demographic characteristics, and the BCPS.

The study’s inclusion criteria encompassed women who were at least 20 years old, exhibited no indications of abnormal breast lesions during clinical examination, and possessed the necessary literacy skills to complete the questionnaire. The study excluded individuals who met the following criteria: a confirmed diagnosis of breast cancer as documented in medical records, a history of cosmetic breast surgery, and impairment in communication skills related to hearing and speaking, and an inability to physically, cognitively, or mentally respond to questions.

Socio-demographic questionnaire

The questionnaire included questions regarding socio-demographic factors such as age, spouse age, marital status, educational level, job, income, breast cancer history, history of hormone therapy, family history of breast cancer and menopause status.

Breast cancer perception scale

Taylan et al. (2021) in Turkey [ 23 ] developed the BCPS. The present tool is grounded in the theoretical framework of the HBM and comprises a set of 24 items designed to assess women’s perceptions of breast cancer. The construct comprises six sub-dimensions, including Perceived knowledge, Perceived treatment belief, Perceived need for health check, Perceived stigma, Perceived fear and Perceived risk, which are assessed using a five-point Likert scale. The responses span a spectrum from strongly disagree (1) to strongly agree (5). The scale’s validity and reliability have been empirically established within the specific demographic of Turkish women in 2021. The lower bound of the scoring range for this questionnaire is 24, while the upper bound is set at 120. A positive correlation exists between higher scores and a greater level of women’s perception of breast cancer [ 23 ].

Sample size determination

It is imperative to ascertain the appropriate sample size to conduct the factor analysis procedure. According to a rule of thumb, the classification of sample size for EFA is as follows: a sample size of 50 is considered very poor, 100 is poor, 200 is fair, 300 is good, 500 is very good, and 1000 is excellent [ 32 ]. To ensure the reliability and validity of the results, it is necessary to have an appropriate sample size when conducting factor analysis. This study incorporated the guidelines proposed by Nunnally [ 33 ], which recommend a sample size of 5 to 10 samples for each instrument question to facilitate the generalizability of the findings to the broader community. Under these guidelines, it was deemed appropriate to utilize a sample size of 10 samples for each case, taking into account that the tool consisted of 24 items. Therefore, initially, a minimum of 240 samples were considered necessary. Nevertheless, it is imperative to take into account the effectof the cluster sampling technique employed in the research. The cluster sampling method introduces a factor of intra-cluster correlation that necessitates its inclusion in the calculation of the sample size [ 33 ]. To address this issue, a design effect of 1.5 was employed to modify the sample size. Due to a 10% attrition rate, the sample size has consequently expanded to encompass a total of 372 participants.

Statistical analysis

The statistical analysis was conducted using the SPSS software package (version 16, IBM Corp., Armonk, NY, USA), STATA14 (Statcorp, College Station, Texas, USA), and R software 4.2 (Psych package). To examine socio-demographic data, descriptive statistics were employed, including frequency (percentage) for qualitative variables, minimum and maximum values, and mean ± standard deviation (SD) for quantitative variables. The evaluation encompassed methodological testing, which involved the assessment of reliability, validity, and responsiveness. Exploratory factor analysis (EFA) and confirmatory factor analysis (CFA) techniques were employed to assess construct validity on a larger scale. The direct oblimin method was employed in the EFA. Bartlett’s test for sphericity and KMO’s test for assessing the adequacy of scale content and sample size were conducted. The CFA methodology was employed to assess the factor structure and factor loadings of the scale. In conclusion, an assessment was conducted to evaluate the reliability of the study, specifically focusing on internal consistency, test-retest reliability, and measurement error. Finally, the presence of ceiling and floor effects was assessed.

Methodological testing according to the COSMIN checklist

• Reliability

Reliability refers to the extent to which a measurement is devoid of any errors that may arise during the measurement process. The evaluation of reliability primarily involves the assessment of three key characteristics: internal consistency, test-retest reliability, and measurement error [ 29 ].

Internal consistency

Internal consistency refers to the extent of interconnectedness among items. It serves as an estimation of the correlation level between the variables that constitute the intended structure or instrument [ 29 ]. The internal consistency of the instrument as a whole and its six subscales was assessed using both Cronbach’s alpha coefficient and McDonald’s omega coefficient. A minimum threshold of 0.7 was deemed necessary for both Cronbach’s alpha and MacDonald’s Omega coefficients to establish satisfactory internal consistency [ 34 ].

Test–retest reliability

Test-retest reliability refers to the extent to which the outcomes of a patient with identical health conditions remain consistent over a while [ 29 ]. Following the guidelines outlined in the COSMIN manual, a test-retest procedure was conducted with a minimum interval of two weeks. This time frame was chosen to prevent participants from recalling their previous responses and to account for any potential changes in their health status [ 29 ]. To achieve the intended objective, a survey was administered to a cohort of 30 female participants on two separate occasions, with a 14-day gap between each administration. The resulting scores were subsequently utilized to assess the reliability of the survey instrument through the application of the intraclass correlation coeficient (ICC). A reliability coefficient greater than 0.7 was deemed advantageous [ 34 ].

Measurement error

Measurement error is considered one of the key indicators of measurement and test reliability. In essence, it refers to the presence of both systematic and random errors in the patient’s score, which cannot be attributed to genuine variations in the construct under consideration. The calculation of the standard error of measurement (SEM) involves the use of the formula (SEM = SD√1-ICC), where SD represents the standard deviation [ 34 ]. The concept of the smallest detectable change (SDC) pertains to the minimum magnitude of an individual score change that can be accurately interpreted as a genuine change. The calculation of the SDC is determined by employing the formula (SDC = SEM*1.96*√2). A reduced level of the SDC corresponds to an increased level of measurement sensitivity [ 34 ].

Validity refers to the extent to which a given instrument accurately measures the specific characteristic it is designed to assess [ 29 ].

Face validity

Face validity is a concept that pertains to the extent to which the items within an instrument, specifically the HR-PRO, accurately represent the underlying construct that is intended to be measured [ 29 ]. The researchers conducted an assessment of face validity using both qualitative and quantitative methods. To conduct a qualitative assessment of face validity, a sample of 10 women from health centers in Tabriz City was selected using a convenience sampling method. This sample then examined the initial questionnaire. The participants assessed the quality, level of difficulty, lack of relevance, and degree of ambiguity of the items. To evaluate the face validity, item impact scores were quantitatively computed. During this phase, the aforementioned participants assessed each item on a 5-point Likert scale, ranging from “completely important” to “not at all important,” with scores ranging from 5 to 1 (representing “completely important,” “important,” “moderately important,” “slightly important,” and “not important,” respectively). The impact score is calculated by multiplying the Frequency (expressed as a percentage) by the Importance (Impact Score = Frequency (%) × Importance). Items with an impact score exceeding 1.5 were deemed appropriate and were subsequently retained for further stages of analysis [ 35 ].

Content validity

The degree to which the content of an HR-PRO instrument effectively represents the construct that is intended to be assessed [ 29 ]. Both qualitative and quantitative methods were used to examine the validity of the content of the questionnaire. To assess the credibility of the qualitative content, a group of ten experts, including three experts in reproductive health, two specialists in midwifery, three specialists in medical-surgical nursing, and two specialists in community health nursing, were invited to provide their insights and opinions on topics considering grammar, vocabulary choice, item arrangement, and scoring.

The inclusion criteria of the experts to determine content validity include voluntary participation, faculty members with the rank of assistant professor and above, PhDs of midwifery/nursing and individuals with clinical experience in breast cancer. The process of assessing quantitative content validity involves the calculation of two measures: the content validity ratio (CVR) and the content validity index (CVI) [ 36 ]. To fulfill the objective, a questionnaire comprising questions organized into two overarching categories was distributed to each expert. In the initial phase, the participants assessed the items using a 3-point Likert scale (necessary, useful but not necessary, not necessary) to ascertain the CVR, which was computed using the following mathematical expression:

CVR= (Ne-N/2)/ (N/2).

Where, “Ne” represents the count of experts who have chosen the “necessary” option, and N denotes the total number of experts. Regarding Lawshe table, a CVR > 0.62 for a sample size of 10 individuals, confirms the essentiality of the items under investigation [ 37 ].

Subsequently, the CVI review underwent evaluation by an identical group of 10 experts. Concerning this matter, questions have been raised regarding the three criteria of relevance, clarity, and simplicity for each item. These criteria have been assessed using a four-point Likert scale, which includes options such as irrelevant, somewhat relevant, relevant, and completely relevant. The assessment is based on the content validity index [ 38 ] developed by Waltz and Basel. The level of relevance, clarity, and simplicity was assessed by experts based on their subjective evaluation, and then the CVI was computed using the following formula:

CVI = number of experts giving a rating of 3 and 4 / total number of experts.

CVIs higher than 0.79, between 0.70 and 0.79, and less than 0.70 were considered acceptable, in need of correction, and unacceptable, respectively [ 39 ].

Construct validity

The concept of construct validity pertains to the extent to which the scores obtained from an HR-PRO instrument align with the anticipated hypotheses. This alignment can be observed in terms of internal relationships, relationships with scores obtained from other instruments, or differences between relevant groups. This assessment is contingent upon the assumption that the HR-PRO instrument possesses validity. The concept of validity pertains to the extent to which a given measure accurately assesses the construct it is intended to measure. The three aspects encompassed in this study are as follows: structural validity, which pertains to the internal relationships within the construct; hypothesis testing; and cross-cultural validity, which focuses on the relationships with scores on other instruments or differences between relevant groups [ 29 ].

Structural validity

The suitability of the data for EFA was assessed by employing the Kaiser-Meyer Olkin (KMO) criterion and Bartlett’s test of sphericity. The KMO test is a statistical measure that quantifies the proportion of variance in the questions that can be attributed to the primary factors. Typically, values falling within the range of 0.8–1 are indicative of adequate data sampling to conduct factor analysis. However, when the value of the statistic falls below 0.7, it indicates that the sample size is insufficient, necessitating the implementation of corrective actions [ 40 ].

Bartlett’s test of sphericity is a frequently employed statistical test to assess the appropriateness of data for factor analysis. The significance of this test serves as an indicator of the suitability of the data for factor analysis [ 40 ]. The process of extracting factors from the 24 items of the questionnaire was conducted using the principal component analysis method, employing varimax rotation (direct oblimin). The determination of the number of factors was based on the criterion of an Eigenvalue greater than 1 and the examination of the Scree plot. In this analysis, a minimum factor loading threshold of 0.3 was utilized for the extraction of factors. In contrast, CFA employs the maximum likelihood method to estimate the model’s fit indices, and a range of indices are utilized to assess the appropriateness of the model. This study assessed the adequacy of the model by employing the indicators outlined below [ 41 ]:

Root mean score error of approximation (RMSEA < 0.08), standardized root mean square residual (SRMR < 0.10), normed Chi 2 (x 2 / df) < 5, comparative fit indices including comparative fit index (CFI > 0.90), Bentler-Bonett Normed Fit Index (NFI) > 0.90, Relative fit index (RFI) > 0.90 and Tucker-Lewis Index (TLI) > 0.90.

Hypothesis testing

The process of hypothesis testing is characterized by its continuous and iterative nature. Hypotheses serve as a means to express the anticipated direction and magnitude of correlations or differences between the construct under investigation and other constructs. As the number of hypotheses tested regarding the alignment between the data and pre-existing hypotheses increases, a greater amount of evidence supporting construct validity is accumulated [ 29 ]. To assess construct validity, an analysis of the hypotheses that were previously formulated was conducted. In this study, it was postulated that the BCPS would exhibit a strong correlation with other subjective scales, such as quality-of-life instruments for cancer patients (QLICP-BR V2.0). Hence, confirmation of the desired hypothesis can be achieved when the Pearson correlation coefficient exceeds 0.5. Furthermore, the study computed the floor and ceiling effect (F/C) as well as the proportion of women who achieved the minimum and maximum scores. F/C effects refer to the percentage of individuals who achieve the highest (ceiling) or lowest (floor) possible scores within a specific domain. These effects serve as indicators of a questionnaire’s sensitivity and coverage at the extreme ends of the scale. In the context of this study, a problematic scenario is defined as a situation where 15% or more of the respondents fall into either the ceiling or floor category [ 42 ].

Responsiveness

Measurement instruments should possess a high degree of sensitivity to detect and accurately capture changes, while also demonstrating a responsive nature to promptly reflect these changes. According to the COSMIN checklist, responsiveness refers to the capacity of an HR-PRO instrument to accurately identify alterations in the construct being assessed over a while [ 29 ]. Terwee et al. [ 34 ] argue that responsiveness can be assessed by examining the relationship between the smallest detectable change (SDC) and the minimally important change (MIC). If the value of SDC is less than MIC, then the responsiveness is confirmed.

Interpretability

Interpretability refers to the extent of qualitative significance, specifically the minimally important changes (MIC) within the instrument. The extent to which quantitative instrument scores or changes in scores can be attributed to qualitative meaning, such as clinical or commonly understood meanings, has been discussed [ 29 ]. The estimation of the minimum important change (MIC) was conducted by dividing the standard deviation (SD) by two, as outlined in the study conducted by Norman et al. [ 43 ].

Descriptive characteristics of participants

This study involved the participation of 372 women. The participants were randomly split into two groups, one group of 172 participants for EFA and another group of 200 participants for CFA. The average age was 52.7 and 52.3 years with a standard deviation of 9.5 and 8.5 years in EFA and CFA group, respectively. A significant majority of the individuals surveyed were married (78.5%, 80.5% in EFA and CFA group, respectively), and 73.8%, 61.0% of them identified themselves as housewives in EFA and CFA group, respectively. Table  1 provides a summary of the additional socio-demographic characteristics of the two groups of participants.

In the present study, the mean (SD) of the entire BCPS scale was 61.66 (8.44), with a range of obtainable scores from 24 to 120. The mean (SD) for the six extracted factors, namely Perceived fear, Perceived knowledge, Perceived treatment belief, Perceived risk, Perceived need for a health check, and Perceived stigma, were respectively 8.28 (4.02), 11.63 (3.79), 10.5 (2.41), 9.37 (2.12), 10.19 (3.22), and 12.15 (2.65).

The values of Cronbach’s alpha and McDonald’s omega (95% CI) were found to be 0.68 and 0.70 (0.66 to 0.74), respectively. These results suggest that the questionnaire exhibits satisfactory internal consistency. Also, the ICC (95% CI) gave a value of 0.97 (0.94 to 0.99). Standard error of measurment is a statistical metric utilized to assess the accuracy and consistency of a given measurement. The SEM value in this study was determined to be 1.36. This implies that upon conducting multiple iterations of the measurement, it is anticipated that the recorded values will fall within a range of ± 1.36 units with the actual score. Moreover, the SDC denotes the smallest detectable change that can be consistently detected by the measuring apparatus. Within the given framework, the value of SDC was ascertained to be 3.73 units. This implies that any deviation in the measured quantity that is less than 3.73 units may not be discernible due to measurement errors and can be regarded as insignificant (Table  2 ).

The tool’s content and face validity were assessed using the CVI (CVI range: 0.87–1.00), CVR (CVR range: 0.75–1.00), and impact scores (3.06–4.00), which yielded values of 0.98, 0.95, and 3.70, respectively.

The construct validity investigation involved conducting an EFA on a set of 24 items. The resulting Kaiser-Meyer-Olkin (KMO) value of 0.71 was obtained at a statistically significant level of less than 0.001, indicating that the sample size in the current study was sufficient. Furthermore, the statistical analysis revealed that Bartlett’s test of sphericity yielded a significant result ( p  ≤ 0.001), indicating that factor analysis was appropriately conducted based on the correlation matrix in the sample under investigation.

The scree plot displayed the results of EFA, revealing six factors with eigenvalues > 1. These factors collectively accounted for 52% of the variance (Fig.  1 ). Table  3 presents the extracted components alongside the corresponding items associated with each factor. The initial factor examined in this study was Perceived fear, comprising a set of four questions that contributed to 13.60% of the overall variance. The second factor, referred to as Perceived knowledge, comprises a set of four questions that collectively account for 11.00% of the overall variance. The third and fourth factors were Perceived treatment belief and Perceived risk, respectively. These factors consisted of four and two questions, respectively, and accounted for 8.9% and 6.4% of the variance. The fifth factor, referred to as Perceived need for a health check, consists of four questions with a variance of 6.3%. Additionally, the sixth factor, known as “Perceived stigma,” comprises four questions that account for 5.8% of the total variance (Fig.  2 ). After preliminary psychometric testing, 24 items were factor-analysed providing a 22-item, six-factor scale. It is important to highlight that, in the original instrument, questions 9 and 23, respectively addressed the notions that “Breast cancer treatment does not change the outcome” and “The risk for breast cancer is higher in those with a family history of breast cancer,” were excluded from the EFA in the present study due to their factor loadings being less than 0.3. Consequently, there was a reduction in the number of instrument questions from 24 items in the original instrument to 22 items.

Factor load scree plot of the items for determining the number of extracted factors of the Iranian version of BCPS

Factor structure model of the BCPS based on CFA. All factor-item relationships were significant ( P  < 0.05). Fc1: Perceived fear, Fc2: Perceived knowledge, Fc3: Perceived treatment belief, Fc4: Perceived risk, Fc5: Perceived need for health check, Fc6: Perceived stigma

CFA was employed to examine the six factors that were derived from EFA. The findings indicate that the model has attained a level of fit that is considered optimal, thereby providing support for confirming the factor structure. The indicator \(\raisebox{1ex}{${x}^{2}$}\!\left/ \!\raisebox{-1ex}{$df$}\right.\) is found to be 2.029 (χ2 = 393.781, df = 194, P-value < 0.001). Additionally, the fit indexes TLI, CFI, NFI, and RFI all exceed the threshold of 0.9. Furthermore, the RMSEA and SRMR index values are both equal to 0.055, indicating a valid model.

Hypothesis testing, responsiveness and interpretability

The hypothesis confirmation involved the computation of Spearman’s correlation coefficient between the BCPS and QLICP-BR V2.0, and the resulting coefficient of 0.55 indicated a statistically significant correlation. To assess the feasibility of the tool, the ceiling effect in the overall score of BCPS was found to be 0.3%. In the sub-domains, the ceiling effects for Perceived fear, Perceived knowledge, Perceived treatment belief, Perceived risk, Perceived need for a health check, and Perceived stigma were determined to be 2.2%, 0.4%, 0.3%, 1.1%, 0.3%, and 0.8%, respectively. The floor effect in the overall score of BCPS was observed to be 0.5%, while in the specific subdomains, it was found to be 26.9%, 3.5%, 3.2%, 1.3%, 4.6%, and 0.8%, respectively. It is noteworthy to mention that the MIC refers to a specific threshold value that delineates the smallest alteration in the measured parameter that holds clinical or practical significance. In this particular instance, the MIC was determined to be 3.92 units. Specifically, the study reveals that the MIC value surpasses the SDC value by 3.73 units. This observation indicates that the Iranian version of the measurement tool is sufficiently responsive. Put simply, the measurement tool can accurately identify and assess changes that hold significance or relevance within the given measurement framework. SEM of this study’s findings generally implies that the measuring device used exhibits a satisfactory level of precision. The comparison between the SDC and the MIC values further demonstrates the instrument’s capacity to consistently identify significant variations in the measured variable (Table  2 ).

The aim of this study was to assess the measurment properties of the Breast Cancer Perception Scale (BCPS) in Iranian women, according to the COSMIN checklist for the first time. The findings of the research substantiate the validity, reliability, responsiveness, and interpretability of the BCPS, which is grounded in the health belief model (HBM) when applied to Iranian women.

The HBM has been widely employed in the study of breast cancer diagnostic behaviors for an extended period [ 25 , 26 , 27 ]. The BCPS is a novel screening tool for breast cancer that has been developed utilizing the HBM [ 23 ]. Despite the presence of various tools in this domain, such as “belief in mammography” and “breast self-examination,” “perceived sensitivity toward breast cancer,” “perceived benefits and obstacles of mammography usage,” “fear of breast cancer (FBC)”, and “fatalism regarding cancer “, these instruments appear to lack practicality as they assess factors individually and fail to encompass all relevant domains. The BCPS demonstrates utility in its comprehensive coverage of various domains, particularly in assessing previously unmeasured aspects such as perceived knowledge, and mental measurements, including the perceived need for a health check, perceived stigma, perceived fear, and perceived risk [ 23 ].

Breast cancer perception is one of the most important indicators for preventing breast cancer and adopting protective behaviors against breast cancer. Proper perception of breast cancer serves as a motivator for women to adhere to breast cancer prevention methods. Despite the existence of various preventive and diagnostic methods for breast cancer, none of these methods will be effective until there is a proper perception of breast cancer. Therefore, the BCPS scale, considering important dimensions such as Perceived knowledge, Perceived treatment belief, Perceived need for health check, Perceived stigma, Perceived fear and Perceived risk, can play an important role in creating preventive behaviors against breast cancer [ 23 ].

In the current investigation, EFA was conducted on a set of 24 items of the instrument. The analysis yielded six factors, namely Perceived fear, Perceived knowledge, Perceived treatment belief, Perceived risk, Perceived need for a health check, and Perceived stigma. These factors aligned with the original instrument and collectively accounted for approximately 52% of the variance, while in the original instrument, they accounted for 74.36% of the variance [ 23 ]. To assess the validity of the instrument, the KMO measure was computed, yielding a value of 0.71. Additionally, the adequacy of the model was verified through Bartlett’s test, which yielded a significance level of 0.77 in the original study [ 23 ]. Furthermore, the reliability of the instrument was obtained ranging from 0.64 to 0.94 by using Cronbach’s alpha, and these values align with the original study’s reported range of 0.81 to 0.95 [ 23 ].

In the present study, the initial factor extracted during the exploratory EFA was identified as perceived fear. The influence of perceived fear on women’s adoption of protective behaviors against breast cancer can be observed. The findings of various studies indicate that a significant majority of women encounter fear regarding the potential diagnosis of breast cancer and the subsequent possibility of undergoing a mastectomy, either unilaterally or bilaterally, at some point in their lives [ 44 , 45 ]. In a similar vein, a separate study indicated that women who exhibited a heightened FBC were found to undergo mammograms less frequently within a one-year timeframe in comparison to their counterparts [ 46 ]. In the study conducted by Aguirre et al., it was observed that young Spanish women exhibited a notable level of fear towards breast cancer, despite not expressing a general sense of concern regarding the disease. According to the study [ 47 ], it was found that 25.3% of the participants reported above-average FBC, while 59.7% reported high FBC. This finding implies that breast cancer may elicit a particularly strong sense of fear, even among young women who do not have significant health issues and have a low objective risk. This observation aligns with the findings of previous research [ 48 , 49 ]. Furthermore, when comparing the findings of this study to previous research conducted within the past two decades, it becomes evident that the extent of fear induced by breast cancer has remained relatively stable despite favorable epidemiological advancements such as reduced mortality rates and enhanced treatment options [ 50 ].

The second factor that was extracted in this study related to perceived knowledge. Perceived knowledge encompasses biases, such as unrealistic optimism and implicit confidence [ 51 ]. The concept of perceived knowledge pertains to an individual’s level of knowledge and is not directly associated with one’s knowledge, specifically regarding breast cancer. The WHO has advocated for the adoption of breast cancer knowledge and awareness as a viable medical strategy for the management of breast cancer. This approach is deemed essential and should be universally implemented, irrespective of financial constraints. In this regard, Izanloo et al. demonstrated that a significant majority of the participants, totaling over 84%, exhibited a lack of knowledge regarding breast cancer and screening tests among 14- to 84-year-old Iranian women. The primary factors cited by women as barriers to undergoing screening tests were the absence of discernible symptoms or issues and their perception of the test’s necessity. A significant difference was observed in the level of women’s knowledge of breast cancer and screening tests concerning factors such as employment status, education level, and family history of breast cancer. However, no significant difference was found in the level of knowledge among women based on their marital status or income level [ 52 ]. Moreover, a study conducted by Mehejabin et al. sought to examine the level of knowledge regarding various aspects of breast cancer among women in Bangladesh. The findings revealed that a majority of the participants, exceeding 50%, possessed a limited understanding of the risk factors associated with breast cancer, indicating a significant lack of knowledge [ 53 ].

Perceived treatment beliefs constituted an additional factor. Perceived belief in treatment can be influenced by various factors, including women’s spiritual and religious beliefs, familial history of breast cancer treatment, and prior experiences with breast cancer treatment [ 45 ]. Concerning this matter, individuals’ perceptions of their treatment beliefs have the potential to influence their engagement in protective behaviors. The findings of the study conducted by Mehejabin et al. indicate that a considerable proportion of women hold the belief that breast cancer can be detected at a young age. Furthermore, the participants held the belief that early diagnosis of the disease could lead to its potential cure [ 53 ]. The aforementioned findings align with the results obtained from a research study carried out at Dhaka Medical College Hospital in Bangladesh, wherein 51.43% of female participants indicated that early detection of breast cancer leads to a potential cure [ 54 ]. Suwankhong and Liamputtong have posited that religious belief significantly influences individuals’ decision-making processes concerning treatment options and risk factors associated with breast cancer [ 55 ]. Yew et al., found a significant difference in the perceptions of breast cancer risk with religious affiliations, specifically between the Muslim and Buddhist cohorts. The impact of Islam and Buddhism on individuals’ lifestyles and health-related behaviors has been significant. Muslim women exhibited a profound conviction in the authority of God (Allah), whereas Buddhist women commonly invoked their karma [ 56 ].

Perceived risk, identified as an additional extracted factor, holds a significant influence over breast cancer protective behavior [ 45 ]. Observing the challenges and distress experienced by our beloved individuals throughout breast cancer treatment amplifies both the perceived fear and the perceived risk of breast cancer [ 57 ]. The primary determinant of health behaviors for breast cancer prevention, diagnosis, and control is the perceived risk. Conversely, establishing concordance between the perceived risk and the objective risk of developing breast cancer results in a more accurate and actual perception of the risk. Consequently, it can serve as motivation for fostering suitable health behaviors [ 58 ]. Hajian et al. [ 59 ], examined the perceived risk of breast cancer among 800 Iranian women about the actual risk. The findings of the study revealed that both women with a low and high risk of breast cancer exhibited a significantly higher perceived risk of the disease compared to their actual risk. This finding suggests a significant inclination towards pessimism in the assessment of breast cancer risk, consistent with previous research conducted in this domain [ 60 , 61 ].

The results of this study also identified the perceived need for a health check as an additional extracted factor. One of the main obstacles to breast cancer screening among women is a diminished perception of the necessity for health screening. Women typically do not perceive the necessity of seeking medical attention unless they possess knowledge regarding the specific symptoms associated with a particular ailment [ 62 ]. Research findings indicate that women residing in developing nations often tend to decline the notion of early diagnosis and screening for breast cancer, primarily influenced by their cultural and personal beliefs. The aforementioned factor has a detrimental impact on the implementation of preventive measures aimed at mitigating the risk of breast cancer [ 63 ]. Therefore, variations in the perceived need for health screening can potentially impact individuals’ engagement in breast cancer protective behaviors. The scoping review study conducted by Omidi et al. examined the current status of breast cancer screening strategies and indicators among Iranian women. The study findings revealed that the prevalence rates of screening methods, including BSE, CBE, and mammography, among Iranian women were reported as 0-79.4%, 4.1–41.1%, and 1.3–45%, respectively [ 64 ].

Based on the HBM theory, Darvishpour et al. [ 25 ] posited that the decision of women to engage in breast cancer screening is influenced by factors such as self-efficacy and perceived benefits. Conversely, the presence of perceived barriers diminishes the likelihood of self-examination. According to Khazir et al., individuals who perceive fewer barriers are more likely to engage in breast cancer screening programs [ 65 ]. Abdel-Aziz et al. conducted a study utilizing EFA to examine the perceived barriers faced by women with breast cancer. Their findings indicate that personal fears, specifically fear of doctors/examiners, fear of screening results, and fear of the hospital environment, are the primary obstacles preventing women from utilizing free screening. These fears were identified as the main barriers based on their eigenvalue values, which exceeded 3.335, representing 30.4% of the barriers identified [ 66 ].

The final factor that was extracted pertains to the concept of perceived stigma. The symbolic significance of breasts for women stems from their association with childbirth, breastfeeding, childrearing, and sexual desires. Consequently, the symbolic significance associated with this phenomenon may impede women from accessing necessary healthcare services, interventions, or diagnostic procedures [ 67 ]. Furthermore, the absence of discussion regarding breast cancer and screening behaviors may be associated with societal stigmatization and cultural taboos surrounding the topic of breasts [ 68 ]. It is well known that stigma plays a significant role in the psychological distress that breast cancer-diagnosed women experience. The occurrence of rejection, blame, or devaluation is what defines the social phenomenon known as stigma. This arises from the personal experience, perception, or rational expectation of an unfavorable social evaluation directed toward an individual or a collective entity [ 69 ]. It was found that around 76.7% and 8.7% of breast cancer survivors reported moderate and high levels of stigma, respectively [ 70 ]. Based on prior research, it has been established that the perceived stigma among individuals diagnosed with breast cancer has significant adverse consequences for their overall well-being and health-related outcomes. These repercussions encompass various aspects such as sexual dysfunction, depressive symptoms, compromised sleep quality, reduced inclination to seek medical assistance, and diminished quality of life [ 71 ].

In terms of clinical application, the use of this scale is considered to save time and enable early detection of breast cancer during assessment. Utilizing this screeninig tool by health care providers improves a quick and comprehensive attitude toward breast cancer perception among women. The main advantage of BCPS is that it helps more subjective measurements compared to other scales in this area. In addition, its goal is to evaluate the relationship between breast cancer and diagnostic behaviors for breast cancer (such as maintaining healthy behaviors like diet, physical activity, mammography, breast self-examination, and clinical breast examination), knowledge about breast cancer, and family history of breast cancer [ 23 ].

Strength and limitation

The present study possesses several notable strengths. Firstly, it is the first study to assess BCPS among Iranian women. Secondly, the study adheres to the COSMIN checklist, ensuring methodological rigor. Additionally, the study incorporates both the DP and FB methods for the translation process, effectively addressing the limitations associated with the FB method. Lastly, the study includes a comparative analysis of BCPS with other versions.

However, it is important to acknowledge the limitations of the current study. These limitations include the lack of criterion validity calculations due to the lack of a gold standard, the lack of an assessment of cross-cultural validity and the possibility of bias from participants’ tendency to give socially desirable answers when using self-reported measures. As we conducted this study in Tabriz-Iran, should be cautious about the generalizability of findings. In conclusion, it is recommended that future research endeavors employ a larger sample sizeand assess the measurment properties in diverse contexts.

The obtained findings suggest that the Iranian version of the BCPS demonstrates satisfactory measurment properties for assessing the perception of breast cancer among Iranian women. Furthermore, it exhibits favorable responsiveness to clinical variations. The assessment of women’s perceptions of breast cancer is imperative for the advancement of preventive behaviors against this disease. The present scale can be employed for the assessment of the association between breast cancer and behaviors related to breast cancer diagnosis, including breast self-examination, clinical breast examination, mammography, and the adoption of healthy behaviors such as diet and exercise. Finally, it can be utilized to investigate the correlation between breast cancer knowledge and family history.

Data availability

The datasets generated and/or analyzed during the current study are not publicly available due to the limitations of ethical approval involving the patient data and anonymity, but are available from the corresponding author upon reasonable requests.

Abbreviations

Breast Cancer Perception Scale

Consensus-Based Standards for the Selection of Health Status Measurement Instruments

Breast Cancer

Global Cancer Incidence Mortality and Prevalence

World health organization

Eastern Mediterranean Region

Age-standardized rate

Hormone replacement therapy

Visual Analouge Scale

Health Belief Model

Breast self-examination

Clinical Breast Examination

Health related-patient reported outcomes

Dual pannel

Forward-backward

Exploratory factor analysis

Confirmatory factor analysis

Intra-class Correlation Coefficient

standard deviation

Content validity index

Content validity ratio

Standard error of measurment

Smallest detectable change

Minimal important change

Degree of freedom

Average variance extracted

Kaiser-Meyer-Olkin

Root mean squared error of approximation

Comparative fit index

Tucker–Lewis index

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Acknowledgements

We should thank the Vice-chancellor for Research of Tabriz University of Medical Sciences for their financial support and the invaluable participation of women would be appreciated.

This Study is funded by Tabriz University of Medical Sciences (grant number: 69930). The funding source had no role in the design and conduct of the study, and decision to this manuscript writing and submission.

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MM, SMA, MH contributed to the design of the study. SMA, ESK, MM has written the first draft of this article and MAJ Analyzed and data. All authors have critically read the text and contributed with inputs and revisions, and all authors read and approved the final manuscript.

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The current study was approved by the Ethics Committee of Tabriz University of Medical Sciences [ref: IR.TBZMED.REC.1401.390]. Written Informed consent to participate in the study was obtained from all the participants before enrolment. Permission to use the BCPS was obtained by sending an email from the original designer of the instrument. All methods were carried out in accordance with relevant guidelines and regulations.

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Mashayekh-Amiri, S., Jafarabadi, M.A., Hosseinzadeh, M. et al. Measurement properties of the Iranian version of the breast cancer perception scale (BCPS) according to the COSMIN checklist. BMC Cancer 24 , 743 (2024). https://doi.org/10.1186/s12885-024-12493-2

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Cation channels are up-modulated in CAFs and involved in fibroblast activation. a Heatmap (bottom) reporting normalized enrichment scores (NES) for gene sets related to voltage gated channels and bar plot (top) reporting mean + sd, as calculated by GSEA on three independent datasets of prostate cancer patient-derived CAFs vs. matched NPFs. b qRT-PCR showing CACNA1H , CACNB1 , CACNB3 , SCN2A , SCN1B , and KCNS3 expression levels in an independent setting of three CAF and matched NPF cultures. Data were reported as relative expression compared to NPF and were representative of three independent experiments. c Western blotting analysis showing selected ion channel protein levels in a pair of matched CAFs and NPFs. β-actin was used as endogenous control. d qRT-PCR indicating relative expression levels of α-SMA, FAP and COL1A1 in NPF#1, NPF#2 and WPMY-1 fibroblasts exposed to CM of DU145 cells with respect to control fibroblasts. e Western blotting showing α-SMA, FAP and COL1A1 expression levels in WPMY-1 fibroblasts exposed or not to CM of DU145 cells. β-tubulin was used as endogenous control. f Immunofluorescence microphotographs showing α-SMA (green) and Col1a1 (red) expression in NPF and NPF exposed to CM of DU145 cells. Nuclei counterstained with DAPI (blue). Scale bar, 50 µm. g Cation channel mRNA expression levels in NPF#1, NPF#2 and WPMY-1 fibroblasts exposed to CM of DU145 cells with respect to untreated fibroblasts. h Western blotting displaying cation channel protein levels in NPF#1 and WPMY-1 fibroblasts exposed or not to CM of DU145 cells. β-tubulin was used as endogenous control. Results reported in the figure represent the mean (+ SD) of three independent experiments. * p  < 0.05, ** p  < 0.01, *** p  < 0.005, Student’s t-test

Activated fibroblasts show increased membrane conductance for potassium, sodium and calcium

Electrophysiological recordings were performed on control and activated WPMY-1 fibroblasts. The two groups were not different in any of the passive properties like membrane capacitance (control: 31.4 ± 2.4 pF, n  = 11; activated: 32.1 ± 3.8 pF; n  = 12; p  = 0.96, Mann–Whitney test) or membrane resistance (control: 221. ± 27 MΩ, n  = 11; activated: 212 ± 28 MΩ; n  = 12; p  = 0.82, Mann–Whitney test). In control condition, upon progressively more depolarized potentials (see methods), fibroblasts showed a very consisted current pattern in which only the sustained potassium current (K + steady) was detected (Fig.  2 a). On the contrary, for activated fibroblasts we could also record an inward current (Fig.  2 a) that was sensitive to both flecainide, a voltage gated sodium channel inhibitor (untreated: 609.25 ± 115.16 pA, n  = 4; flecainide: 351.75 ± 62.16 pA; n  = 4; p  = 0.036, paired t-test, Fig.  2 b), and nifedipine, a voltage gated calcium channel inhibitor (untreated: 449.25 ± 90.82 pA, n  = 4; nifedipine: 164.00 ± 26.99 pA; n  = 4; p  = 0.037, paired t-test, Fig.  2 b), suggesting that this current was mediated by influx of sodium and calcium. While the potassium steady current was present in the majority of the recorded fibroblasts in both control and activated condition (control: 100%, n  = 11; activated: 91%, n  = 12), the inward current as well as a fast-inactivating potassium current was functionally detected only in some of the activated fibroblasts (inward: 67%, n  = 12; K + inactivating: 25%, n  = 12, Fig.  2 c). The current density at the peak value of the IV-plot for the K + steady current was significantly higher for the activated group compared to the control condition (control: 33.9 ± 2.8 pA/pF, n  = 11; activated: 50.2 ± 7.2 pA/pF; n  = 11; p  = 0.04, Multiple unpaired t-test, Fig.  2 d). The peak current density recorded for in the activated group for the K + inactivating current was 17.8 ± 7.1 pA/pF ( n  = 3) while for the inward current it was 7.6 ± 2.9 pA/pF ( n  = 8). Overall these data suggest that activated fibroblasts show increased membrane conductance for potassium, sodium and calcium, consistently with the mRNA and protein content analysis (Fig.  1 ).

Activated fibroblasts show increased membrane conductance for potassium, sodium and calcium. a Representative Voltage-clamp recordings of inward and outward currents from activated and control WPMY-1 cells fibroblasts. A schematic of the applied protocol is shown in the insert. Upon activation, an inward current as well as a fast-inactivating outward current can be detected in fibroblasts. b The inward current shows significant sensitivity to both flecainide (2.5 μM) and nifedipine (2.5 μM) when applied to the bath solution. c Pie chart summarizing the percentage of cells expressing the main currents detected in A upon depolarization in both the control and the activated group. d The IV plot for the K + steady shows a significant increase in the current density in the activated group compared to the control condition. The I-V plot for the inward current is also displayed

Antiarrhythmics counteract the activated state of prostate CAFs

Aiming to assess the functional role of voltage-gated cation channels in supporting fibroblast activation, a panel of pharmacological blockers of sodium, calcium and potassium channels, commonly used as antiarrhythmics, were tested as potential agents to revert CAF activated state (Table  1 ). The treatment of CAFs with sub-toxic doses of antiarrhythmics (Additional Fig. 1) was sufficient to induce a variable reduction of fibroblast activation markers, such as α-SMA and Col1a1 protein levels as a function of the drug and concentration (Fig.  3 a). Among the several features and functions of CAFs, increased cell motility, ECM remodeling and deposition are definitely some of the main characteristics distinguishing them form NPFs [ 33 ]. The treatment with antiarrhythmics was sufficient to reduce CAF migratory ability, as indicated by the significantly reduced wound closure upon treatment (Fig.  3 b and Additional Fig. 2a). In addition, p-FAK, which is a crucial mediator of cell migration and spindle orientation, was reduced, although to a variable extend, upon treatment of CAFs with antiarrhythmics (Fig.  3 c), confirming that such drugs impaired CAF migratory capability by hindering focal adhesion formation. CAF-mediated ECM deposition and mechanical remodeling resulted to be affected by antiarrhythmics as well. Specifically, as depicted in Fig.  3 d, the degree of contraction of gels exerted by antiarrhythmics-treated CAFs was significantly reduced compared to that of untreated CAFs. In addition, the secretion of Col1a1 and fibronectin in the extracellular environment was largely abrogated upon the treatment of CAFs with antiarrhythmics (Additional Fig. 2b), indicating a reduction of CAF-induced ECM deposition. The reason behind the reduced ECM remodeling capability of treated CAFs was investigated by measuring MMP2 levels in the CM of CAFs exposed to antiarrhythmics. As shown by western blotting (Fig.  3 e), CAF-released MMP2 was significantly lower in CM of treated cells, as indicated by the reduced levels of secreted active- and pro-MMP2 in the CM of CAFs treated with antiarrhythmics compared to untreated CAFs, which was paralleled by an increased intracellular accumulation of pro-MMP2 in treated CAFs.

Antiarrhythmics counteract the activated state of prostate CAFs. a Western blotting and relative quantification showing protein levels of fibroblast activation markers (α-SMA and COL1A1) in CAFs treated for 48 h with sub-toxic doses of antiarrhythmics. β-tubulin was used as endogenous control. b Bar plots showing the wound-healing rate assessed by scratch assay on CAFs exposed to antiarrhythmics. Data are reported as wound healing ratio at 24 h compared to 0 h point. c Representative immunofluorescence microphotographs (upper panel) showing the organization of β-actin cytoskeleton (green) and p-FAK (red) in CAFs treated with verapamil as compared to untreated. Scale bar, 50 μm. Western blotting analysis (lower panel) showing p-FAK, FAK protein levels in CAFs treated with sub-toxic doses of antiarrhythmics. β-tubulin was used as endogenous control. d Representative images (upper panel) showing 3D-collagen gel remodeling of CAFs exposed to sub-toxic doses of antiarrhythmics. NPFs were used as negative control. The dotted lines define gel areas. Bar plots (lower panel) showing ECM remodeling ratio of treated CAFs assessed by 3D-collagen gel assay. Data are reported as ECM remodeling ratio at 48 h compared to 0 h point. e Western blotting showing levels of pro-MMP2 and active-MMP2 in CM from CAFs exposed or not to sub-toxic doses of antiarrhythmics and, pro-MMP2 intracellular levels in treated cells. Gapdh was used as endogenous control for cell lysate. Results reported in the figure represent the mean (+ SD) of three independent experiments. * p  < 0.05, ** p  < 0.01, *** p  < 0.005, Student’s t-test

Antiarrhythmics affect PCa cell growth by impairing CAF function

It has been well established that CAFs induce PCa progression by supporting tumor cell growth as well as by enhancing tumor cell motility and the switch from an epithelial-like to a more mesenchymal-like phenotype [ 10 , 34 , 35 , 36 ]. In this regard, the impact of antiarrhythmics on CAF-PCa cross-talk was evaluated by performing indirect co-culture experiments using CM (Fig.  4 a). As shown in Fig.  4 b,c and Additional Fig. 3a, CM of CAFs induced a slight increase of PCa cell growth, which was more pronounced in DU145 and LNCaP compared to PC3 cells [ 37 ]. In this regard, controversial information has been reported regarding the ability of CAFs to promote cell growth of PCa cell lines. In fact, high-metastatic potential PCa cell lines, like PC3 cells, were reported to be less responsive to the proliferative effects induced by CAFs compared to low-metastatic potential cell lines, like LNCaP. However, such a moderate enhancement was significantly abolished in all the PCa cell models upon exposure to CM of antiarrhythmic-treated CAFs, especially with CM-CAF-nifedipine (calcium-channel blocker) and CM-CAF-flecainide (sodium channel-blocker), partially recapitulating the tumor cell growth suppression exerted by CM of NPFs (Fig.  4 b,c and Additional Fig. 3a). Consistent with cell growth findings, cell cycle analysis of DU145 cells reveled that exposure to CM of CAFs increased the S-phase cell fraction and reduced the G1-phase cell fraction compared to untreated cells, while an opposite trend was observed after exposure to CM of NPFs (Fig.  4 d). CM of CAFs treated with the different antiarrhythmics, with the exception of amiodarone, was sufficient to recapitulate the effects mediated by CM-NPF on DU145 cell cycle distribution, resulting in an accumulation of cells in G1-phase and a reduction of S-phase cell population (Fig.  4 d).

Antiarrhythmics affect PCa cell growth by impairing CAF function. a Schematic representation of CM experiment work-flow (Created with Biorender.com). b Graph reporting the growth of DU145 cells cultured with CM from CAFs treated or not with antiarrhythmics, or CM from NPFs at different time points (24, 48, 72 h). c Graph reporting the growth of LNCaP cells cultured with CM from CAFs treated or not with antiarrhythmics, or CM from NPFs at different time points (24, 48, 72 h). d Cell cycle phase distribution of DU145 cells cultured with CM from CAFs treated or not with antiarrhythmics, or CM from NPFs at 72 h until treatment. Results reported in the figure represent the mean (+ SD or ± SD) of three independent experiments. * p  < 0.05, ** p  < 0.01, *** p  < 0.005, Student’s t-test

Antiarrhythmics affect PCa cell plasticity by impairing CAF function

As a typical CAF-induced aggressive trait, EMT markers were evaluated in the castration-resistant (DU145) and in the androgen-sensitive PCa cell model (LNCaP) exposed to CM of CAFs treated or not with antiarrhythmics. As expected, DU145 cell exposure to CM-CAF mediated a transition from a more epithelial-like toward a more mesenchymal-like phenotype, as highlighted by the down-regulation of epithelial markers ( CDH1 /E-cadherin and CTNNB1 /β-catenin) and the increased expression of mesenchymal ones ( VIM /vimentin and SNAI1 /Snail) at both the mRNA and protein levels (Fig.  5 a and Additional Fig. 3b). Conversely, the expression levels of VIM /vimentin and SNAI1 /Snail were generally reduced in DU145 cells exposed to CM of CAF-treated with antiarrhythmics (Fig.  5 b and Additional Fig. 3c), mimicking the EMT suppressive effect exerted by CM-NPF, although an enhancement of epithelial markers by CM of antiarrhythmic-treated CAFs was consistently observed only at the protein levels (Fig.  5 a,b). The ability of antiarrhythmics to affect CAF-induced PCa plasticity was particularly appreciable in the androgen-sensitive model, where the treatment generally reverted the expression of both epithelial ( CDH1 /E-cadherin and CTNNB1 /β-catenin) and mesenchymal markers ( VIM /vimentin and SNAI1 /Snail) in LNCaP cells, which was more appreciable at the protein levels (Fig.  5 c,d and Additional Fig. 3d,e). Focusing on those antiarrhythmics that showed a greater capability to impact on ECM remodeling process mediated by CAFs (Fig.  3 f) and to induce a partial reversal of EMT in co-culture experiments (Fig.  5 a, b), we evaluated whether the treatment could revert CAF-promoted migratory boost on DU145 cells. As indicated in the representative photomicrographs and bar graph, DU145 cells exposed to CM of CAFs displayed a high and rapid capacity to close the wound. Conversely, the CM of CAFs treated with nifedipine or flecainide significantly reduced DU145 cell migration capability, showing a wound-healing ratio to an extent approaching that observed with CM-NPF (Fig.  5 e). These findings suggest that nifedipine and flecainide decrease CAF-mediated pro-migratory boost on DU145 cells, thus confirming the repressive effects of antiarrhythmics on CAF pro-tumor spur. Since CAF-derived cytokines are master regulators of EMT, migration and invasion of cancer cells, we investigated the perturbation induced by antiarrhytmics on CAF secretome profile. Protein profiler analysis reveled an increase in the glycosylation-inhibiting factor (GIF), also known as macrophage migration inhibitory factor, in the CM form CAFs. Upon the treatment with nifedipine, GIF levels decreased in the CM of treated CAFs, bringing them closer to those observed in CM of NPFs. However, no difference in GIF levels was observed in CM of CAFs treated with flecainide compared to untreated CAFs. Additionally, IL-8, which is a well–known promoter of migration and EMT, was found to be increased in CM from CAFs [ 38 ]. In contrast, both nifedipine and flecainide completely abrogated IL-8 release from CAFs, resembling the IL-8 levels observed in the CM of NPFs (Fig.  5 f). These observations indicate that antiarrhythmics perturb CAF protumor effects by reducing tumor-stroma cross-talk, potentially inhibiting the initial phases of the metastatic process, such as EMT and migration. Another interesting role exerted by CAFs is the promotion of stemness in PCs cells [ 34 ]. Thus, we investigated whether the treatment could revert CAF-promoted stemness in DU145 cells. As showed in Fig.  5 g, DU145 cells exposed to CM from untreated CAF displayed a slight increase in the expression of both the stemness markers CD44 and CD133 compared to untreated cells. In contrast, CM from NPF reduced the expression of CD144 and CD133, suggesting a possible inhibition of stemness features in DU145 cells exerted by NPF. Interestingly, treatment with antiarrhythmics partially abolished the stemness-promoting effect of CM from CAF, which was particularly evident for CD133. However, this effect was observed for CD44 only when amiodarone was used (CM-CAF-amio).

Antiarrhythmics affect PCa cell plasticity by impairing CAF function. a - d Western blotting analysis showing E-cadherin, β-catenin, Vimentin and Snail protein amount in DU145 cells (a-b) and LNCaP cells ( c - d ) exposed to CM from NPFs or CM from CAFs treated or not to antiarrhythmics. β-tubulin was used as endogenous control. e Representative bright-field microphotographs (left panel) showing migration rate of DU145 cells exposed to CM from NPFs or CM from CAFs treated or not with nifedipine or flecainide. Scale bar, 100 μm. The dotted lines define the areas lacking cells. Bar plots (right panel) showing the wound-healing rate of DU145 cells upon the indicated treatments, as from the scratch assay. Data are reported as wound healing ratio at 24 h compared to 0 h. f Cytokine and chemokine protein array blots (left panel) of CM from CAFs treated or not with nifedipine or flecainide, and CM from NPFs. Bar plot (right panel) depicts the pixel density of each cytokine or chemokine (mean). The signal intensity of each cytokine or chemokine was expressed relative to the mean of the intensity of the corresponding spots from vehicle control sample. g Western blotting and relative quantification showing the expression of stemness markers (CD133 and CD44) in DU145 cells exposed to CM from CAFs treated or not with antiarrhythmics, or CM from NPFs, with respect to untreated cells. β-tubulin was used as endogenous control. Results reported in the figure represent the mean (+ SD) of three independent experiments. * p  < 0.05, ** p  < 0.01, *** p  < 0.005, Student’s t-test., when calculated against untreated cells

Antiarrhythmics normalize the transcriptome of CAFs

To investigate the perturbation induced by antiarrhythmics at the transcriptome level, gene expression profiling analysis was performed on three independent patient-derived CAF cultures, treated or not treated with nifedipine or flecainide, and matched NPFs as controls. The t-distributed stochastic neighborhood embedding (t-sne) projection of all genes revealed that, even though at moderate physical distance, both nifedipine and flecainide-treated CAFs clustered in between the clearly separated NPFs and CAFs clusters (Fig.  6 a). This suggests that antiarrhythmics polarize CAF transcriptome into a more NPF-like one, which is in trend with the previously shown results suggesting that conversion from a tumor supporting to a tumor suppressing phenotype. Gene set enrichment analysis (GSEA) run using Reactome pathways showed commonalities between nifedipine- and flecainide-treated CAFs (Fig.  6 b and Additional Fig. 4), especially regarding the down-modulation of gene sets related to extracellular matrix organization, collagen formation, TGF-beta signaling, elastic fiber formation and glucose metabolism (Fig.  6 c, Additional Table 1), all processes known to be relevant for CAF activation and function [ 18 ]. Among genes up-regulated in antiarrhythmics-treated CAFs enrichment was observed for gene sets related to lipid metabolism, an aspect that might warrant investigation in future studies (Additional Table 2).

Antiarrhythmics normalize the transcriptome of CAFs. a Scatter plot of t-SNE components showing similarity of transcriptomes of CAFs, NPFs and antiarrhythmics-treated CAFs. b Venn diagram showing overlap between Reactome gene sets enriched (GSEA, NES < 0, FDR p -val < 0.05) in genes down-regulated in CAFs upon nifedipine and flecainide treatments. c Bar plot showing NES of representative gene sets down-regulated in nifedipine- and flecainide-treated CAFs

Antiarrhythmics impair the capability of CAFs to sustain PCa cell growth in vivo

To evaluate the impact of antiarrhythmics on CAF-PCa cross-talk in vivo, PCa xenograft-bearing mice were treated with intra-tumorally administered CM derived from antiarrhythmic-treated CAFs, CAFs or NPFs as control (Fig.  7 a). In accord with the in vitro evidence, CM of nifedipine- or flecainide-treated CAFs significantly attenuated the in vivo growth of PCa tumors compared to CM-CAF, exerting a tumor suppressive effect resembling that of CM of NPF. In addition, CM-CAF-mediated EMT was evaluated in vivo, indicating that tumors exposed to antiarrhythmic-CM CAF showed a higher expression of E-cadherin, similarly to what observed in CM-NPF treated tumors (Fig.  7 b). Tumors explanted from mice exposed to CM of treated CAFs were also characterized by the lowest proliferative rate, as indicated by Ki-67 index, with a 20% reduction compared to that of tumors from CM-CAF group (Fig.  7 c).

Antiarrhythmics impair the capability of CAFs to sustain PCa cell growth in vivo. a DU145 cells were subcutaneously injected into the right flanks of SCID mice. When tumors reached the volume of ~ 100 mm. 3 , mice were randomized into four groups and were intra-tumorally treated for 5 days per 2 weeks with CM from CAFs treated or not with nifedipine or flecainide, or CM from NPFs (see insert on the right for a schematic representation of the experiment). The graph reports tumor volumes along the experiment. Black rows indicate when treatment was administered. Schematic representation of the experimental workflow (created with Biorender.com) ( b ) Western blotting showing E-cadherin levels in PCa tumors excised at the end of the treatment with CM from CAFs treated or not with antiarrhythmics, or CM from NPFs. β-tubulin was used as endogenous control. c Representative bright-field microphotographs (upper panel) showing Ki-67 staining in PCa tumors excised at the end of the treatment with CM from CAFs treated or not with antiarrhythmics, or CM from NPFs. Bar plot (lower panel) showing Ki-67 positive cells in PCa tumors upon the relative treatment. Data were reported as percentage of Ki-67 positive cells with respect to total number of cells. Eight fields were evaluated for each condition. d Representative bright-field microphotographs (upper panel) showing CD31 staining in PCa tumors excised at the end of the treatment with CM from CAFs treated or not with antiarrhythmics, or CM from NPFs. Bar plot (lower panel) showing CD31 positive cells in PCa tumors upon the relative treatment. Data were reported as percentage of CD31 positive cells with respect to total number of cells. Eight fields were evaluated for each condition. e DU145 cells were subcutaneously co-injected with CAFs, CAFs pretreated with nifedipine or flecainide, or with NPFs, into the right flanks of SCID mice. The graph report tumor volumes along the experiment. f Timeline indicating tumor take (n. of tumors/n. of co-injected mice) in the different experimental groups, as from the experiment described in panel e . (Created with Biorender.com)

Given the well-established contribution of CAFs to promote tumor angiogenesis [ 3 ], we investigated whether CM from treated CAFs was able to impair the endothelial network formation in PCa tumors. As indicated in Fig.  7 d, tumors explanted from mice exposed to CM from antiarrhythmic-treated CAFs showed a lower expression of the angiogenesis marker CD31, resembling the anti-angiogenic role exerted by CM of NPF on DU145 cells. Co-injection of DU145 cells with CAFs pretreated with flecainide (DU145 + CAF-fleca) slightly reduced tumor growth compared to DU145 cells injected with untreated CAFs, although not affecting the overall tumor take (Fig.  7 e). However, DU145 cells injected with flecainide-treated CAFs required a longer interval of time to develop palpable tumors in all transplanted mice compared to DU145-CAF group (6/6 animals with palpable tumors at day 30 vs 5/5 animals with palpable tumors at day 20) (Fig.  7 f). In line with NPF tumor suppressive behavior, co-injection of NPFs with DU145 cells resulted in the highest tumor growth delay and lowest xenograft take (0/6 animals with palpable tumors at day 20 after co-injection).

Despite the numerous attempts, cancer-centric therapeutic strategies frequently fail to overcome the malignancy, also due to the presence of a tumor-supportive microenvironment that may promote therapeutic resistance and tumor relapse [ 8 ]. Cancer initiation, progression, metastatic dissemination and multi-drug resistance are processes extensively driven by CAF-cancer cell interactions [ 39 ]. Considering this crucial role of CAFs in cancer outcome, several preclinical studies have shown that blocking CAF function may be beneficial in different cancer types [ 8 ]. However, only a few clinical trials have been conducted so far using agents or strategies specifically designed to target CAFs in cancer patients, showing very limited results. In this regard, sibrotuzumab, a humanized anti-FAP monoclonal antibody was safely administrated in phase I and II clinical trials on advanced tumors with FAP + stroma, although no objective tumor response was observed [ 40 ].

The poor knowledge of the key processes governing CAF biology, together with the complexity in defining univocal markers for this heterogeneous population have impaired the translation of CAF-focused strategies into clinical practice. Therefore, further efforts are needed to fully understand CAF biology and define targetable vulnerabilities. We previously highlighted a possible involvement of cation channels in CAF activation and function, showing that gene sets encoding for calcium, sodium and potassium ion channels were up-modulated in prostate cancer-derived CAFs [ 18 ]. Here, these initial findings were confirmed both at the mRNA and protein level in independent sets of prostate CAFs established from PCa surgical samples or in NPFs experimentally activated in vitro, showing also concordance with CAF-expression profiles from publicly available data sets. Moreover, the electrophysiological recordings showed an increased membrane conductance for potassium, sodium, and calcium in activated fibroblasts. The role of cation channels has been widely studied in physiological and pathological processes, including carcinogenesis. Noteworthy, the carcinogenesis process has been recognized as a certain type of “channelopathy”, due to the functional involvement of cation channels in the main distinctive features acquired by cancer cells, including unlimited proliferation, uncontrolled differentiation and apoptosis, increased cellular motility and secretion [ 41 ].

Multiple lines of evidence pointed out that ion channels have considerable biological significance in PCa development, progression and response to therapy. For instance, the voltage-gated potassium (Kv) 2.1 was found to be upmodulated in PC3 cells and involved in cell migration. Targeting Kv2.1 with stromatoxin-1 or siRNA-mediated approaches significantly inhibited the migration of PCa cells [ 42 ]. Moreover, highly selective voltage-gated sodium channel inhibitors induced the suppression of metastasis from PCa models in vivo [ 43 ]. In addition, calcium channels were found overexpressed during androgen deprivation in PCa, suggesting their involvement in the acquisition of neuroendocrine features [ 44 ]. In this regard, we have to take into consideration that PCa presentation may include very-low risk and clinically indolent tumors, which never metastasize, or high-risk and aggressive tumors characterized by a high rate of metastatization and poor response to treatments [ 45 , 46 ]. The biological mechanisms underlying these different clinical behaviors are not fully understood. Interestingly, the comparison between PCa stroma from indolent and aggressive tumors revealed a prominent difference in terms of transcriptional profile. For instance, bone-remodeling and immune-suppressive signatures have been observed in high-risk PCa stroma, but not in the stroma of indolent PCa samples [ 47 ]. This piece of evidence, together with the experimental prove of the involvement of CAFs in inducing castration-resistance in PCa, suggested that the existence of aggressive traits within the stroma can promote PCa progression toward a more aggressive phenotype. On the other hand, a less tumor-permissive stroma might eventually repress aggressive features of PCa and promote indolent behaviors.

To the best of our knowledge, only a handful of reports showed the involvement of cation channels in CAF biology [ 48 , 49 , 50 ]. In PCa, Vancauwenberghe and colleagues recently described that the alteration of TRPA1-calcium channel in PCa stroma is sufficient to reduce resveratrol-induced apoptosis in PCa cells, highlighting how deregulated ion channels in CAFs can affect PCa response to treatments [ 51 ]. Our work illustrates that antiarrhythmics, used as cation channel blocker agents, are able to counteract the activated state of CAFs and potentially restore a tumor-suppressive phenotype. Although at a different extent as a function of the drug and concentration used, antiarrhythmics modulate the expression of CAF markers and hinder the main tumor-promoting features of reactive prostate CAFs, including motility and capability to remodel the ECM, by reducing focal adhesion formation and MMP-2 secretion. More importantly, the use of antiarrhythmics impaired the tumor-supportive role exerted by CAFs on androgen-sensitive and –castration-resistent PCa cells, reducing their ability to foster cancer cell proliferation, plasticity, stemness, and angiogenesis both in vitro and in vivo. Normalizing activated stroma or restoring a quiescent environment has recently emerged as a valid and attractive anti-cancer CAF-centered strategy [ 8 ]. In fact, instead of depleting the tumor stroma, which could also affect cellular and structural components exerting tumor suppressive functions, reprogramming the microenvironment towards to a more quiescent phenotype should create a less permissive milieu and reduce cancer growth. In this regard, we acknowledge the existence of controversial data regarding the opportunity to reprogram the tumor microenvironment in order to re-stabilize tumor-inhibiting signals. For instance, in preclinical models of pancreatic ductal adenocarcinoma (PDA), where the role of the abundant fibrotic tumor stroma has been largely investigated, it was shown that depleting CAFs by using monoclonal antibodies against CAF markers, such as FAP or α-SMA, conferred resistance to chemotherapy [ 52 ]. Conversely, inducing a transcriptional reprogramming of pancreatic stroma cells through administration of vitamin D receptor ligands was sufficient to re-establish a physiological stroma, thus reducing tumor volume and improving survival in PDA-bearing mice [ 53 ]. Similarly, our data indicated that targeting cation channels in prostate CAFs by antiarrhythmics resulted in a reduction of PCa cell growth in mice as a consequence of a transcriptional reprogramming leading to a shift from a tumor-promoting CAF-phenotype to a tumor-suppressive one. Of note, preclinical studies reported that direct exposure to antiarrhythmics is able to reduce PCa cell proliferation in vitro and in vivo [ 33 ]. Consistent with this, clinical reports suggest that long-term use of antiarrhythmics may confer a benefit by reducing the risk of developing high-grade PCa [ 54 ]. However, while there is currently no evidence indicating a reduction in PCa-specific mortality with the use of antiarrhythmics [ 55 ], an intriguing observation comes from recent research by Fairhurst C. and colleagues. Their study revealed a potential link between the treatment with antiarrhythmics against voltage-gated sodium channels and a modest improvement in cancer-specific survival. This association was identified in a retrospective cohort of cancer patients, encompassing individuals with breast, bowel, or prostate cancer [ 56 ]. The use of antiarrhythmics in the context of PCa may offer a dual benefit by concurrently targeting the tumor and its stromal counterpart, making them a promising strategy for a comprehensive therapeutic intervention in such disease. Furthermore, exploring a drug repositioning strategy has the advantage of potentially reducing the time and costs associated with developing new compounds.

Here, we speculate on the use of antiarrhythmics as a potential repositioning strategy to normalize PCa stroma through the inhibition of voltage-gated cation channels. Our results show that antiarrhythmics are indeed able to modulate CAF-activated phenotype and impair the CAF-mediated pro-tumor boost on PCa cells both in vitro and in vivo.

Availability of data and materials

All data generated or analyzed during this study are included in this published article (and its Additional files) and available from the corresponding author on reasonable request.

Abbreviations

α-Smooth muscle actin

• Cancer-associated fibroblasts

Extracellular matrix

Epithelial-mesenchymal transition

Fibroblast activation protein

Fold change

Gene Set Enrichment Analysis

Matrix metalloproteases proteins

Normalized enrichment score

Normal prostate fibroblasts

• Prostate cancer

Pancreatic ductal adenocarcinoma

Molecular Signature Database

Voltage-gated potassium

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Acknowledgements

This research was supported by Italian Association for Cancer Research (AIRC) grant: Special Program “Innovative Tools for Cancer Risk Assessment and Early Diagnosis”, 5 × 1000, (ED12162 to N.Z.) and by I. Monzino Foundation (to N.Z.).

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Paolo Gandellini and Nadia Zaffaroni contributed equally to this work.

Authors and Affiliations

Molecular Pharmacology Unit, Department of Experimental Oncology, Fondazione IRCSS Istituto Nazionale Dei Tumori, Milan, 20133, Italy

Valentina Doldi, Monica Tortoreto, Stefano Percio & Nadia Zaffaroni

Vita-Salute San Raffaele University, IRCCS San Raffaele Hospital and Scientific Institute, Milan, 20132, Italy

Maurizio Colecchia

Department of Urology, Hospitals of Legnano and Magenta, Milan, 20013, Italy

Massimo Maffezzini

Department of Biosciences, University of Milan, Milan, 20133, Italy

Francesca Giammello, Federico Brandalise & Paolo Gandellini

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Contributions

VD, MT, FB and FG performed experiments. MC and MM provided the clinical samples. SP performed the bioinformatics analysis. VD analyzed data. VD and PG designed the research. VD, PG and NZ wrote the manuscript. PG and NZ provided critical advice for the study and manuscript. NZ acquired the funds. All authors reviewed the manuscript.

Corresponding author

Correspondence to Valentina Doldi .

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Ethics approval and consent to participate.

For human specimens, the study protocol (INT n. 154/16) was approved by the Ethics Committee of IRCCS Istituto Nazionale dei Tumori of Milano in accordance with the declaration of Helsinki. Informed consents were obtained from patients before starting the study. Animal studies were performed in accordance with guidelines of animal care protocols approved by Ethics Committee for animal experimentation of IRCCS Istituto Nazionale dei Tumori of Milano and Italian Ministry of Health (approval code n. 350/2017-PR).

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Supplementary Information

13046_2024_3081_moesm1_esm.pdf.

Additional file 1: Additional Figure 1. Dose-response curves of CAFs exposed to antiarrhythmics for 72 h. Results reported in the figure represent the mean (+SD or ±SD) of three independent experiments.

13046_2024_3081_MOESM2_ESM.pdf

Additional file 2: Additional Figure 2. a. Representative bright-field microphotographs showing migration rate of CAFs exposed to antiarrhythmics Scale bar, 100 μm. The dotted lines define the areas lacking cells. b. Western blotting showing fibronectin and Col1a1 in CM from CAFs treated or not with antiarrhythmics.

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Additional file 3: Additional Figure 3. a. Graph reporting the growth of PC3 cells cultured with CM from CAFs treated or not with antiarrhythmics, or CM from NPFs at different time points (24, 48, 72 hours). b and d. qRT-PCR showing relative expression levels of epithelial markers ( CDH1 and CTNNB1 ) in DU145 cells (b) or LNCaP cells (d) exposed to CM from CAFs treated or not with antiarrhythmics, or CM from NPFs with respect to untreated cells. c and e. qRT-PCR showing relative expression levels of mesenchymal markers ( VIM and SNAI1 ) in DU145 cells (c) and LNCaP cells (e) exposed to CM from CAFs treated or not with antiarrhythmics, or CM from NPFs with respect to untreated cells.

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Additional file 4: Additional Figure 4. Venn diagram showing overlap between Reactome gene sets enriched (GSEA, NES<0, adjusted p-val<0.05) in genes up-regulated in CAFs upon nifedipine and flecainide treatments.

Additional file 5: Additional Table 1. Commonly down-regulated Reactome genesets in antiarrhythmics-treated CAFs.

Additional file 6: additional table 2. commonly up-regulated reactome genesets in antiarrhythmics-treated cafs., additional file 7., rights and permissions.

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Doldi, V., Tortoreto, M., Colecchia, M. et al. Repositioning of antiarrhythmics for prostate cancer treatment: a novel strategy to reprogram cancer-associated fibroblasts towards a tumor-suppressive phenotype. J Exp Clin Cancer Res 43 , 161 (2024). https://doi.org/10.1186/s13046-024-03081-0

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Received : 11 January 2024

Accepted : 25 May 2024

Published : 11 June 2024

DOI : https://doi.org/10.1186/s13046-024-03081-0

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